Cyclopentyl sulfonamide derivatives

ABSTRACT

The present invention provides compounds of formula (I): useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.

[0001] In the mammalian central nervous system (CNS), the transmissionof nerve impulses is controlled by the interaction between aneurotransmitter, that is released by a sending neuron, and a surfacereceptor on a receiving neuron, which causes excitation of thisreceiving neuron. L-Glutamate, which is the most abundantneurotransmitter in the CNS, mediates the major excitatory pathway inmammals, and is referred to as an excitatory amino acid (EAA). Thereceptors that respond to glutamate are called excitatory amino acidreceptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol.Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev.Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, andHonore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acidsare of great physiological importance, playing a role in a variety ofphysiological processes, such as long-term potentiation (learning andmemory), the development of synaptic plasticity, motor control,respiration, cardiovascular regulation, and sensory perception.

[0002] Excitatory amino acid receptors are classified into two generaltypes. Receptors that are directly coupled to the opening of cationchannels in the cell membrane of the neurons are termed “ionotropic”.This type of receptor has been subdivided into at least three subtypes,which are defined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), andkainic acid (KA). The second general type of receptor is the G-proteinor second messenger-linked “metabotropic” excitatory amino acidreceptor. This second type is coupled to multiple second messengersystems that lead to enhanced phosphoinositide hydrolysis, activation ofphospholipase D, increases or decreases in c-AMP formation, and changesin ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci.,14, 13 (1993). Both types of receptors appear not only to mediate normalsynaptic transmission along excitatory pathways, but also participate inthe modification of synaptic connections during development andthroughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol.Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41 (1990).

[0003] AMPA receptors are assembled from four protein sub-units known asGluR1 to GluR4, while kainic acid receptors are assembled from thesub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, MolecularPharmacology 44: 505-510, 1993. It is not yet known how these sub-unitsare combined in the natural state. However, the structures of certainhuman variants of each sub-unit have been elucidated, and cell linesexpressing individual sub-unit variants have been cloned andincorporated into test systems designed to identify compounds which bindto or interact with them, and hence which may modulate their function.Thus, European patent application, publication number EP-A2-0574257discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B.European patent application, publication number EP-A1-0583917 disclosesthe human sub-unit variant GluR4B.

[0004] One distinctive property of AMPA and kainic acid receptors istheir rapid deactivation and desensitization to glutamate. Yamada andTang, The Journal of Neuroscience, Sep. 1993, 13(9): 3904-3915 andKathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634-6647.

[0005] It is known that the rapid desensitization and deactivation ofAMPA and/or kainic acid receptors to glutamate may be inhibited usingcertain compounds. This action of these compounds is often referred toin the alternative as “potentiation” of the receptors. One suchcompound, which selectively potentiates AMPA receptor function, iscyclothiazide. Partin et al., Neuron. Vol. 11, 1069-1082,1993.

[0006] International Patent Application Publication WO 98/33496published Aug. 6, 1998 discloses certain sulfonamide derivatives whichare useful, for example, for treating psychiatric and neurologicaldisorders, for example cognitive disorders; neuro-degenerative disorderssuch as Alzheimer's disease; age-related dementias; age-induced memoryimpairment; movement disorders such as tardive dyskinesia, Huntington'schorea, myoclonus, and Parkinson's disease; reversal of drug-inducedstates (such as cocaine, amphetamines, alcohol-induced states);depression; attention deficit disorder; attention deficit hyperactivitydisorder; psychosis; cognitive deficits associated with psychosis, anddrug-induced psychosis.

[0007] Additional sulfonamide derivatives which potentiate glutamatereceptor function, such as AMPA receptors, have also been disclosed inthe following International Patent Application Publications; WO 99/43285published Sep. 2, 1999; WO 00/06539; WO 00/06537, WO 00/06176, WO00/06159, WO 00/06158, WO 00/06157, WO 00/06156, WO 00/06149, WO00/06148, and WO 00/06083, all published Feb. 10, 2000, WO 00/66546,published Nov. 9, 2000, and WO 01/42203, published Jun. 14, 2001.

SUMMARY OF THE INVENTION

[0008] The present invention provides compounds of formula I:

[0009] wherein

[0010] G represents F or OH;

[0011] R¹ represents an unsubstituted or substituted aromatic group, anunsubstituted or substituted heteroaromatic group, or an unsubstitutedor substituted (5-8C)cycloalkyl group;

[0012] R² represents (1-6C)alkyl, (2-6C)alkenyl, or a group of formulaR³R⁴N in which R³ and R⁴ each independently represent (1-4C)alkyl; and

[0013] p represents the integer 1 or 2;

[0014] or a pharmaceutically acceptable salt thereof.

[0015] The present invention further provides compounds of formula I′:

[0016] wherein

[0017] R¹ represents an unsubstituted or substituted aromatic group, anunsubstituted or substituted heteroaromatic group, or an unsubstitutedor substituted (5-8C)cycloalkyl group;

[0018] R² represents (1-6C)alkyl, (2-6C)alkenyl, or a group of formulaR³R⁴N in which R³ and R⁴ each independently represent (1-4C)alkyl; and

[0019] p represents the integer 1 or 2;

[0020] or a pharmaceutically acceptable salt thereof.

[0021] The present invention further provides a method of potentiatingglutamate receptor function in a patient, which comprises administeringto said patient an effective amount of a compound of formula I.

[0022] The present invention provides a method of treating cognitivedisorders in a patient, which comprises administering to said patient aneffective amount of a compound of formula I.

[0023] In addition, the present invention further provides a method oftreating cognitive deficits associated with psychosis in a patient,which comprises administering to said patient an effective amount of acompound of formula I.

[0024] According to another aspect, the present invention provides theuse of a compound of formula I, or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for potentiating glutamatereceptor function.

[0025] In addition, the present invention provides the use of a compoundof formula I or a pharmaceutically acceptable salt thereof forpotentiating glutamate receptor function.

[0026] The invention further provides pharmaceutical compositionscomprising, a compound of formula I and a pharmaceutically acceptablediluent or carrier.

[0027] This invention also encompasses novel intermediates, andprocesses for the synthesis of the compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0028] In this specification, the term “potentiating glutamate receptorfunction” refers to any increased responsiveness of glutamate receptors,for example AMPA receptors, to glutamate or an agonist, and includes butis not limited to inhibition of rapid desensitization or deactivation ofAMPA receptors to glutamate.

[0029] A wide variety of conditions may be treated or prevented bycompounds of formula I and their pharmaceutically acceptable saltsthrough their action as potentiators of glutamate receptor function.Such conditions include those associated with glutamate hypofunction,such as psychiatric and neurological disorders, for example cognitivedisorders and neuro-degenerative disorders such as Alzheimer's disease;age-related dementias; age-induced memory impairment; cognitive deficitsdue to autism, Down's syndrome and other central nervous systemdisorders with childhood onset, cognitive deficits postelectroconvulsive therapy, movement disorders such as tardivedyskinesia, Huntington's chorea, myoclonus, dystonia, spasticity, andParkinson's disease; reversal of drug-induced states (such as cocaine,amphetamines, alcohol-induced states); depression; attention deficitdisorder; attention deficit hyperactivity disorder; psychosis; cognitivedeficits associated with psychosis, drug-induced psychosis, stroke, andsexual dysfunction. Compounds of formula I may also be useful forimproving memory (both short term and long term) and learning ability.The present invention provides the use of compounds of formula I for thetreatment of each of these conditions.

[0030] The present invention includes the pharmaceutically acceptablesalts of the compounds defined by formula 1. A compound of thisinvention can possess a sufficiently acidic group, a sufficiently basicgroup, or both functional groups, and accordingly react with any of anumber of organic and inorganic bases, and inorganic and organic acids,to form a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt as used herein, refers to salts of the compounds of theabove formula which are substantially non-toxic to living organisms.Typical pharmaceutically acceptable salts include those salts preparedby reaction of the compounds of the present invention with apharmaceutically acceptable mineral or organic acid or an organic orinorganic base. Such salts are known as acid addition and base additionsalts. Such salts include the pharmaceutically acceptable salts listedin Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known tothe skilled artisan.

[0031] Acids commonly employed to form acid addition salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, hydrobromide, iodide,acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate,formate, hydrochloride, dihydrochloride, isobutyrate, caproate,heptanoate, propiolate, propionate, phenylpropionate, salicylate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate,cinnamate, hippurate, nitrate, phthalate, teraphthalate,butyne-1,4-dioate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, phthalate, p-toluenesulfonate,p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate,phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate,citrate, lactate, a-hydroxybutyrate, glycolate, tartrate,benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, 1-naphthalenesulfonate, 2-napththalenesulfonate,1,5-naphthalenedisulfonate, mandelate, tartarate, and the like.Preferred pharmaceutically acceptable acid addition salts are thoseformed with mineral acids such as hydrochloric acid and hydrobromicacid, and those formed with organic acids such as maleic acid, oxalicacid and methanesulfonic acid.

[0032] Base addition salts include those derived from inorganic bases,such as ammonium or alkali or alkaline earth metal hydroxides,carbonates, bicarbonates, and the like. Such bases useful in preparingthe salts of this invention thus include sodium hydroxide, potassiumhydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate,sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

[0033] It should be recognized that the particular counterion forming apart of any salt of this invention is usually not of a critical nature,so long as the salt as a whole is pharmacologically acceptable and aslong as the counterion does not contribute undesired qualities to thesalt as a whole. It is further understood that the above salts may formhydrates or exist in a substantially anhydrous form.

[0034] As used herein, the term “stereoisomer” refers to a compound madeup of the same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

[0035] The term “enantiomeric enrichment” as used herein refers to theincrease in the amount of one enantiomer as compared to the other. Aconvenient method of expressing the enantiomeric enrichment achieved isthe concept of enantiomeric excess, or “ee”, which is found using thefollowing equation:${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

[0036] wherein E¹ is the amount of the first enantiomer and E² is theamount of the second enantiomer. Thus, if the initial ratio of the twoenantiomers is 50:50, such as is present in a racemic mixture, and anenantiomeric enrichment sufficient to produce a final ratio of 70:30 isachieved, the ee with respect to the first enantiomer is 40%. However,if the final ratio is 90:10, the ee with respect to the first enantiomeris 80%. An ee of greater than 90% is preferred, an ee of greater than95% is most preferred and an ee of greater than 99% is most especiallypreferred. Enantiomeric enrichment is readily determined by one ofordinary skill in the art using standard techniques and procedures, suchas gas or high performance liquid chromatography with a chiral column.Choice of the appropriate chiral column, eluent and conditions necessaryto effect separation of the enantiomeric pair is well within theknowledge of one of ordinary skill in the art. In addition, the specificstereoisomers and enantiomers of compounds of formula I can be preparedby one of ordinary skill in the art utilizing well known techniques andprocesses, such as those disclosed by J. Jacques, et al., “Enantiomers,Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L.Eliel and S. H. Wilen,” Stereochemistry of Organic Compounds”,(Wiley-Interscience 1994), and European Patent Application No.EP-A-838448, published Apr. 29, 1998. Examples of resolutions includerecrystallization techniques or chiral chromatography.

[0037] Some of the compounds of the present invention have one or morechiral centers and may exist in a variety of stereoisomericconfigurations. As a consequence of these chiral centers, the compoundsof the present invention occur as racemates, mixtures of enantiomers andas individual enantiomers, as well as diastereomers and mixtures ofdiastereomers. All such racemates, enantiomers, and diastereomers arewithin the scope of the present invention.

[0038] The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

[0039] As used herein the term “bis(pinacolato)diboron” refers to thefollowing structure:

[0040] As used herein, the term “aromatic group” means the same as aryl,and includes phenyl and a polycyclic aromatic carbocyclic ring such as1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, andthe like. Phenyl is the preferred aromatic group.

[0041] The term “heteroaromatic group” includes an aromatic 5-6 memberedring containing from one to four heteroatoms selected from oxygen,sulfur and nitrogen, and a bicyclic group consisting of a 5-6 memberedring containing from one to four heteroatoms selected from oxygen,sulfur and nitrogen fused with a benzene ring or another 5-6 memberedring containing one to four atoms selected from oxygen, sulfur andnitrogen. Examples of heteroaromatic groups are thienyl, furyl,oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl,isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, indolyl, and quinolyl.

[0042] The term (5-8C)cycloalkyl includes cyclopentyl; cyclohexyl,cycloheptyl and cyclooctyl.

[0043] The term “substituted” as used in the term “substituted aromatic,heteroaromatic group, or substituted (5-8C)cycloalkyl group” hereinsignifies that one or more (for example one or two) substituents may bepresent, said substituents being selected from atoms and groups which,when present in the compound of formula I, do not prevent the compoundof formula I from functioning as a potentiator of glutamate receptorfunction.

[0044] It is understood that when R¹ represents an unsubstituted orsubstituted (5-8C)cycloalkyl group, mixtures of cis and trans isomersmay result which can be separated into the individual cis and transisomers by one of ordinary skill in the art, using standard techniquesand procedures such as reverse phase or normal phase high performanceliquid chromatography or flash chromatography, with a suitablestationary phase and a suitable eluent. Examples of suitable stationaryphases are silica gel, alumina, and the like. Examples of suitableeluents are ethyl acetate/hexane, ethyl acetate/toluene,methanol/dichloromethane, and the like. Such individual cis and transisomers are included within the scope of the present invention.

[0045] Examples of substituents which may be present on a substitutedaromatic group, a substituted heteroaromatic group, or a substituted(5-8)C cycloalkyl group include halogen; nitro; cyano; (1-10C) alkyl;(2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;—O—(CH₂)_(t)CN, —O—(CH₂)_(t)NH₂, —O—(CH₂)_(t)NHCOR^(10a),—O—(CH₂)_(t)NHSO₂R^(10a) in which t is an integer of from 1 to 4;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO, OCONR¹³,R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl,pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R¹⁰,R^(10a), R¹¹, R¹² and R¹³ each independently represents hydrogen or(1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogenatom to which they are attached form an azetidinyl, pyrrolidinyl,piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl, furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl;(1-4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴-(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ orNR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.

[0046] The term (1-10C)alkyl refers to a straight or branched alkylchain having from one to ten carbon atoms and includes (1-6C)alkyl and(1-4C)alkyl. Particular values are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, and hexyl.

[0047] The terms “halogen”, “Hal” or “halide” include fluorine,chlorine, bromine and iodine unless otherwise specified.

[0048] The term (1-6C)alkoxy, refers to a straight or branched alkylchain having from one to six carbon atoms attached to an oxygen atom andincludes (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, tert-butoxy, pentoxy, and the like.

[0049] The term (2-10C)alkenyl includes (3-10C)alkenyl, (2-8C)alkenyl,(2-6C)alkenyl and (2-4C)alkenyl. Particular values are vinyl andprop-2-enyl.

[0050] The term (2-10C)alkynyl includes (3-10C)alkynyl, (2-8C)alkynyl,(2-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.

[0051] The term halo(1-10C)alkyl includes fluoro(1-10C)alkyl, such astrifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1-10C)alkyl such aschloromethyl.

[0052] The term (2-4C)alkylene includes ethylene, propylene andbutylene. A preferred value is ethylene.

[0053] The term -(1-4C)alkyl(3-8C)cycloalkyl includes the following:

[0054] The term -(1-4C)alkylaromatic includes the following:

[0055] Examples of values for R⁹ are hydrogen, methyl, ethyl, propyl,isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2-pyrrolidinyl, morpholino or 2-tetrahydrofuryl.

[0056] R⁹ is preferably (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl,pyrrolidinyl, morpholino or tetrahydrofuryl.

[0057] R^(10a) is preferably methyl, ethyl, propyl, 2-propyl and butyl,with methyl and 2-propyl being preferred.

[0058] Examples of values for R¹⁵ are hydrogen, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl,2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl,2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

[0059] X¹ preferably represents O, CO, CONH or NHCO.

[0060] z is preferably 0.

[0061] Particular values for the groups (CH₂)_(y)X¹R⁹ and (CH₂)_(z)X³R¹⁵include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such asmethoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy,including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy,including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl,such as formyl and ethanoyl.

[0062] Examples of particular values for y are 0 and 1.

[0063] Examples of particular values for z are 0, 1, 2 and 3.

[0064] Examples of particular values for t are 1 and 2, with 2 beingpreferred.

[0065] L^(a) and L^(b) preferably each independently represents CH2.

[0066] X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONHor OCH₂CONH, with a bond, O, and CONH being especially preferred.

[0067] Preferably the group (CH₂)_(y)X¹R⁹ represents CHO; COCH₃, OCH₃;OCH(CH₃)₂; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl,t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropylor cyclopentyl; NHCOCOOCH₃; or 2-tetrahydrofurylmethoxy.

[0068] Preferably the group (CH₂)_(z)X³R¹⁵ represents NH₂; CH₂NH₂;(CH₂)₂NH₂; (CH₂)₃NH₂; CONH₂; CONHCH₃; CON(CH₃)₂; N(C₂H₅)₂; CH₂OH;CH(OH)CH₃; CH(OH)CH₂CH₂; CHO; COCH₃; COOH; COOCH₃; CH₂NHCOOC(CH₃)₃;(CH₂)₂NHCOOC(CH₃)₃; SO₂NH₂; NHSO₂CH₃; NHSO₂CH(CH₃)₂; a group of formula(CH₂)₂NHSO₂R¹⁵ in which R¹⁵ represents CH₃, CH₂CH₃, CH(CH₃)₂, (CH₂)₂CH₃,(CH₃)₃CH₃, benzyl, CH₂CF₃, 2-methoxycarbonylethyl, cyclohexyl,10-camphoryl, phenyl, 2-fluorophenyl, 4-fluorophenyl,2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,1-(2-dimethylamino)naphthyl or 2-thienyl; CH(OH)CH₂NHSO₂CH₃;(CH₂)₃NHSO₂CH(CH₃)₂; COCH₂N(OCOC(CH₃)₂SO₂CH₃; COCH₂NHSO₂CH₃;(CH₂)₂NHCOR¹⁵ in which R¹⁵ represents CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,phenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 2-methoxyphenyl,4-methoxyphenyl, 2-thienyl, CH═CH, CH═CHCN, OCH₃ or O(CH₂)₃CH₃.

[0069] Examples of particular values for (L^(a))_(n)-X²-(L^(b))_(m) area bond, O, NH, S, SO, SO₂, CO, CH₂, COCH₂, COCONH, CH(OH)CH₂, CONH,NHCO, NHCONH, CH₂O, OCH₂, OCH₂CONH, CH₂NH, NHCH₂ and CH₂CH₂, with abond, CONH, and CH₂O being especially preferred.

[0070] R¹⁴ is preferably an unsubstituted or substituted phenyl,naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl,pyrimidyl benzothienyl or benzothiazolyl group with unsubstituted orsubstituted phenyl being preferred.

[0071] Examples of particular values for R¹⁴ are phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,4-iodophenyl, 2,3-difluoro-phenyl, 2,4-difluorophenyl,3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,4-cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl,4-methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl,2-prop-2-enylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-bromomethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl,2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetylphenyl,3-acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl,2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-butoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl,3-(1-hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl,2-(1-hydroxypropyl)phenyl, 4-(1-hydroxypropyl)phenyl,2-(1-hydroxy-2,2-dimethyl-propyl)phenyl, 4-trifluoromethoxyphenyl,2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl,4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3-aminopropyl)phenyl,4-carboxyphenyl, 4-carbamoylphenyl, 4-N-methylcarbamoylphenyl,4-N,N-dimethylcarbamoylphenyl, 2-isopropylaminomethylphenyl,4-t-butoxycarbonylaminomethylphenyl,4-(2-isopropoxy-carboxamido)ethylphenyl,4-(2-t-butoxycarboxamido)ethyl-phenyl, 4-isopropylsulfonylaminophenyl,4-(2-methane-sulfonylamino)ethylphenyl,4-(2-ethylsulfonylamino)ethyl-phenyl,4-(3-isopropylsulfonylamino)propylphenyl,4-(1-(2-(2-propane)sulfonylamino)propyl)phenyl,4-(2-propylsulfonyl-amino)ethylphenyl,4-(2-isopropylsulfonylamino)ethylphenyl,4-(2-butylsulfonylamino)ethylphenyl,4-(1-isopropyl-sulfonylaminomethyl)ethylphenyl,4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl,4-(2-(2,2,2-trifluoroethyl)-sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonylamino)-ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylaminoy)-ethylphenyl,4-(2-N,N-dimethylaminosulfonylamino)-ethylphenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluoro-phenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethyl-phenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoro-methylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(1-(2-(2-methoxy-carbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl,4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl,4-(N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl,4-(2-(2-thienylcarboxamido)ethyl)phenyl, thien-2-yl,5-hydroxy-methylthien-2-yl, 5-formylthien-2-yl, thien-3-yl,5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2-bromothien-3-yl,fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl,3-bromoisoxazol-5-yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl,5-methylisoxazol-3-yl, 5-hydroxymethylisoxazol-3-yl,5-methyl-3-phenylisoxazol-4-yl, 5-(2-hydroxyethyl)isoxazol-3-yl,5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl,5-N-methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl,3-bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl,4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl,4-carboxythiazol-2-yl, imidazol-1-yl, 2-sulfhydryl-imidazol-1-yl,[1,2,4]triazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl,2-ethyltetrazol-5-yl, 2-isopropyl-tetrazol-5-yl,2-(2-propenyl)tetrazol-5-yl, 2-benzyl-tetrazol-5-yl, pyrid-2-yl,5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl,5-trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl,6-methylpyridazin-3-yl, 6-methoxypyrazin-3-yl, pyrimidin-5-yl,benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl.

[0072] Examples of an unsubstituted or substituted aromatic orheteroaromatic group represented by R¹ are unsubstituted or substitutedphenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as3-pyridyl).

[0073] More preferably, R¹ represents 2-naphthyl or a group of formula

[0074] in which

[0075] R²⁰ represents halogen; nitro; cyano; (1-10C) alkyl;(2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;—O—(CH₂)_(t)CN, —O—(CH₂)_(t)NH₂, —O—(CH₂)_(t)NHCOR^(10a),—O—(CH₂)_(t)NHSO₂R^(10a) in which t is an integer of from 1 to 4;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO, OCONR¹³,R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl,pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R¹⁰,R^(10a), R¹¹, R¹² and R¹³ each independently represents hydrogen or(1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogenatom to which they are attached form an azetidinyl, pyrrolidinyl,piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl;(1-4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴-(L^(a))_(n)-X²-(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ orNR¹ ⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and

[0076] R²¹ represents a hydrogen atom, a halogen atom, a (1-4C)alkylgroup or a (1-4C)alkoxy group.

[0077] Examples of particular values for R²⁰ are fluorine, chlorine,bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, 1,1-dimethylethyl, cyclopentyl, cyclohexyl,3-hydroxycyclopentyl, 3-oxocyclopentyl, methoxy, ethoxy, propoxy,2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido,1-butanoylamido, t-butylcarboxamido, acryloylamido,2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy,morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido,cyclobutylcarboxamido, cyclopentyl-carboxamido, cyclohexylcarboxamido,cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino,piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl,pyrid-2-yl, pyrid-3-yl, pyriddyl, pyrimidin-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2-yl,4,5-dihydro-4-methoxy-carbonyl-5,5-dimethylthiazol-2-yl,benzothien-2-yl, benzothiazol-2-yl, phenyl, 2-fluorophenyl,3-fluorophenyl, 2,3-difluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 2-methylphenyl,4-methylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,4-(2-cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyl,4-formylphenyl, 3-acetyl-phenyl, 4-acetylphenyl, 4-carboxyphenyl,2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl,4-(1-hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl,4-(2-aminoethyl)-phenyl, 4-(3-aminopropyl)phenyl,4-(2-acetylaminoethyl)-phenyl, 4-t-butoxycarboxylaminoethyl)phenyl,4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino,4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonyl-aminoethyl)phenyl,4-(2-ethylsulfonylaminoethyl)phenyl,4-(2-propylsulfonylaminoethyl)phenyl,4-(2-butylsulfonyl-aminoethyl)phenyl,4-(2-isopropylsulfonylaminoethyl)phenyl,4-(1-hydroxy-2-methanesulfonylaminoethyl)phenyl,4-(2-dimethylaminosulfonylaminoethyl)phenyl,4-(1-(2-(2-propyl)sulfonylaminopropyl)phenyl,4-(2-(2,2,2-trifluoro-ethyl)sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonyl-aminoethyl)phenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4-carbamoylphenyl,4-methyl-carbamoylphenyl, 4-dimethylcarbamoylphenyl,4-(2-(2-methylpropaneamido)ethyl)phenyl,4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido,2-fluorobenzamido, 3-flurobenzamido, 4-fluorobenzamido,2,4-difluorobenzamido, 3-chlorobenzamido, 4-chlorobenzamido,4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3-methylbenzamido,4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido,4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido,3-trifluoromethylbenzamido, 4-trifluoromethylbenzamido,2-fluoro4-trifluoromethyl-benzamido, 2-methoxybenzamido,3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido,4-phenylphenyl-carboxamido, 4-benzylcarboxamido,4-phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy,2-fluoro-benzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonylamino)ethyl)phenyl,4-(2-phenylacetamido)ethyl)phenyl,4-(methanesulfonylaminoethanoyl)phenyl,4-(N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl,2-thienylcarboxamido, 2-furylcarboxamido,3-(5-methyl-isoxazolyl)carboxamido, 5-isoxazolylcarboxamido,2-benzothienylcarboxamido, 4-(5-methyl-3-phenylisoxazolyl)-carboxamido,4-pyridylcarboxamido, 2-(5-nitrofuryl)-carboxamido,2-pyridylcarboxamido, 6-chloro-2-pyridyl-carboxamido,2-thienylsulfonamido, 2-thienylmethylamino, 3-thienylmethylamino,2-furylmethylamino, 3-furylmethylamino, 3-acetylureido and2-(2-thienyl)ethylureido.

[0078] Examples of particular values for R²¹ are hydrogen and chlorinewith hydrogen being preferred. R²¹ is preferably ortho to R²⁰.

[0079] Examples of particular values for R¹ are 2-naphthyl,4-bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl,4-isopropyl-phenyl, 4-isobutylphenyl, 4-t-butylphenyl, 4-methoxyphenyl,4-isopropoxy-phenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl,4-(2-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)phenyl,4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)-phenyl,4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl,4-(piperidin-1-yl)phenyl, 3-chloro-4-piperidin-1-ylphenyl,4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3-fluoro-phenyl)phenyl,4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl,4-(4-formylphenyl)phenyl, 4-(4-methylphenyl)phenyl, and4-(2-methoxyphenyl)phenyl. Additional examples of particular values forR¹ are shown in table 1 below. TABLE 1 A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

T

U

V

W

X

Y

Z

Aa

Ab

Ac

Ad

Ae

Af

Ag

Ah

Ai

Aj

Ak

Al

A m

An

Ao

Ap

[0080] The compounds of formula I can be prepared by one of ordinaryskill in the art, for example, following the procedures set forth belowin Schemes I-VII. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. All substituents, unlessotherwise specified are as previously defined.

[0081] In Scheme I, step A, the compound of structure (1) is combinedwith the ketone of structure (2) under standard Grignard conditions wellknown in the art to provide the alcohol (3), for example see JerryMarch, “Advanced Organic Chemistry: Reactions, Mechanisms, andStructure,” Fourth Edition, John Wiley & Sons, (1992) pages 920-929.More specifically, for example, magnesium turnings are added to asuitable organic solvent, such as anhydrous THF under an atmosphere ofnitrogen. A small amount of compound (1) is added along with an iodinecrystal and a catalytic amount of dibromoethane. The reaction is heatedwith vigorous stirring to initiate the Grignard formation. A total ofabout 1.1 equivalents of compound (1) is added dropwise to the reaction.The reaction is then allowed to cool to room temperature and about 1.06equivalents of ketone (2) is added dropwise to the reaction. Thereaction mixture is then heated at reflux for about 2 hours and allowedto cool to room temperature overnight. The alcohol (3) is then isolatedusing standard techniques. For example, saturated ammonium chloride isadded to precipitate the salts. The organic layer is decanted off andthe remaining salts are rinsed with ether which is combined with thefirst organic layer. The combined organics are concentrated under vacuumand the residue is taken up in a suitable organic solvent, such as ethylacetate, dried over potassium carbonate, filtered, and concentratedunder vacuum to provide crude alcohol (3). The crude material can thenbe purified using standard techniques, such as chromatography on silicagel with a suitable eluent, such as hexane/ethyl acetate to providepurified alcohol (3).

[0082] In Scheme 1, step B the alcohol (3) is dehydrated under standardconditions to provide the compound (4). For example, the alcohol (3) isdissolved in a suitable organic solvent, such as toluene and treatedwith p-toluenesulfonic acid. The reaction mixture is heated at refluxfor about 4 hours and water is removed using a Dean-Stark trap. Thereaction mixture is then allowed to cool to room temperature andconcentrated under vacuum. The crude residue is taken up in a suitableorganic solvent, such as methylene chloride, washed with water, driedover potassium carbonate, filtered, and concentrated under vacuum. Thecrude product (4) can be purified by chromatography on silica gel with asuitable eluent, such as hexane/methylene chloride.

[0083] In Scheme 1, step C the compound (4) is epoxidized underconditions well known in the art to provide the epoxide (5). Forexample, about 3 equivalents m-chloroperbenzoic acid is addedportionwise to about 5 equivalents of sodium fluoride in a suitableorganic solvent, such as methylene chloride. The reaction mixture isallowed to stir for about 30 minutes at room temperature and compound(4) is added to the mixture in one portion. The reaction mixture is thenallowed to stir for about 2 to 4 hours at room temperature, and then isfiltered. The filtrate is washed with 1 N sodium hydroxide, water, driedover potassium carbonate, filtered, and concentrated under vacuum toprovide the crude epoxide (5). This crude material can be purified usingsilica gel chromatography with a suitable eluent, such ashexane/methylene chloride to provide the purified epoxide (5).

[0084] In Scheme I, step D, the poxide (5) is opened under standardconditions to provide the azide (6). For example, 1.08 equivalents ofepoxide (5) dissolved in a suitable organic solvent, such as DMF, isadded dropwise at room temperature to a mixture of sodium azide inwater. The reaction is heated at 90° C. with stirring for about 8 to 12hours. The mixture is then poured into water and extracted with asuitable organic solvent, such as ether. The organic layer is washedwith water, dried over potassium carbonate, filtered, and concentratedunder vacuum to provide the azide (6).

[0085] In Scheme I, step E, the azide (6) is converted to the amine (7)under conditions well known in the art. For example, azide (6) isdissolved in a suitable organic solvent, such as toluene and addeddropwise to a suitable reducing agent, such as Red-Al® (available fromAldrich Chemical Company, Milwaukee, Wis.) under a nitrogen atmosphereat room temperature. The reaction mixture is allowed to stir for 1 to 4hours and then is poured into water. The aqueous is extracted with asuitable organic solvent, such as ethyl acetate. The organic extractsare combined, rinsed with water, dried over anhydrous potassiumcarbonate, filtered, and concentrated under vacuum to provide the crudeamine (7). This crude material can be purified by chromatography onsilica gel with a suitable eluent, such as methylene chloride/methanolto provide purified amine (7).

[0086] In Scheme I, step F, the amine (7) is converted to thesulfonamide of compound (8) under conditions well known in the art. Forexample, amine (7) is dissolved in a suitable organic solvent. Examplesof suitable organic solvents include methylene chloride,tetrahydrofuran, and the like. The solution is treated with a slightexcess of a suitable base, and then cooled to about −78° C. to about 0°C. Examples of suitable bases include triethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),and the like. To the stirringsolution is added one equivalent of LgSO₂R². The term “Lg” as usedherein refers to a suitable leaving group. Examples of suitable leavinggroups include, Cl, Br, and the like. Cl is the preferred leaving group.The reaction mixture is stirred at about 0° C. to about 50° C. for about0.5 hours to about 16 hours. The sulfonamide (8) is then isolated andpurified by techniques well known in the art, such as extractiontechniques and chromatography. For example, the mixture is washed with10°/sodium bisulfate, the layers separated and the aqueous extractedwith several times with a suitable organic solvent, such as methylenechloride. The organic extracts are combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue is thenpurified by flash chromatography on silica gel with a suitable eluentsuch as ethyl acetate/hexane to provide the sulfonamide (8).

[0087] In Scheme 1, step G, the sulfonamide (8) is converted to compoundof formula Ia under standard conditions well known in the art. Forexample, compound (8) is dissolved in a suitable organic solvent, suchas methylene chloride and the solution is cooled to about −78° C. underan inert atmosphere, such as nitrogen. To this solution is added slowly,about one equivalent of diethylaminosulfur trifluoride (DAST) dissolvedin a suitable organic solvent, such as methylene chloride with stirring.The reaction is then allowed to warm to room temperature and thecompound of formula Ia is then isolated and purified using techniquesand procedures well known,,in the art, such as extraction techniques andchromatography. For example, the reaction is diluted with water andmethylene chloride. The layers are separated and the organic layer iswashed with water, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to provide the crude compound of formula la.This crude material can then be purified by standard techniques, such asrecrystallization from a suitable eluent, or flash chromatography orradial chromatography on silica gel, with a suitable eluent, such ashexane/ethyl acetate or methylene chloride to provide purified compoundof formula Ia.

[0088] In Scheme IA, step A, the compound of structure (9) is amidatedto provide the sulfonamide of structure (10) in a manner analogous tothe procedure set forth in Scheme I, step F.

[0089] In Scheme IA, step B, the sulfonamide (10) is deprotected understandard conditions to provide the alcohol of structure (11). Forexample, the sulfonamide (10) is dissolved in a suitable organicsolvent, such as ethanol, treated with a suitable hydrogenationcatalyst, such as palladium on carbon and placed under a hydrogenatmosphere at about 60 psi for about 8 to 16 hours. The reaction mixtureis then filtered and the filtrate is concentrated under vacuum toprovide the alcohol (11).

[0090] In Scheme IA, step C, the alcohol (11) is oxidized underconditions well known in the art to provide the ketone of structure(12). For example, the alcohol (11) dissolved in a suitable organicsolvent, such as methylene chloride and treated with about 1.1 to 1.5equivalents of a suitable oxidizing reagent, such as pyridiniumchlorochromate (PCC). The reaction mixture is allowed to stir for about2 to 8 hours and is then filtered through Celite®. The filtrate iswashed with water, dried over potassium carbonate, filtered, andconcentrated under vacuum to provide the crude ketone (12). The ketone(12) can be purified by chromatography on silica gel with a suitableeluent, such as methylene chloride/ethyl acetate to provide the purifiedketone (12).

[0091] In Scheme IA, step D, the ketone (12) is combined with thecompound of structure (1) under standard Grignard conditions in a manneranalogous to the procedure set forth in Scheme I, step A above toprovide the alcohol of structure (8′). It is understood by one ofordinary skill in the art that a mixture of cis/trans isomers will beobtained in this reaction. These isomers can be 'separated usingstandard separation techniques well known in the art such aschromatography on silica gel with a suitable eluent, such as ethylacetate/hexane. Alternatively, the cis/trans mixture can be carried onto step E below and the mixture can then be separated.

[0092] In Scheme IA, step E, the alcohol (8′) is fluorinated in a manneranalogous to the procedure set forth in Scheme I, step G above toprovide the compounds of formula Ia″.

[0093] In Scheme II, step A the compound (1) is combined with compound(2a) under standard Grignard conditions well known in the art to providethe alcohol (3) as described above in Scheme I, step A.

[0094] In Scheme II, step B, the compound (2a) is reduced underconditions well known in the art to provide the amines (7) and (7a). Forexample, compound (2a) is dissolved in a suitable organic solvent, suchas ethanol, a catalytic amount of a suitable catalyst, such as palladiumon carbon is added, and the reaction mixture is placed under hydrogen atabout 60 psi for about 8 to 12 hours. The reaction mixture is thenfiltered through Celite® and the filtrate is concentrated under vacuumto provide the crude mixture of (7) and (7a). The compounds (7) and (7a)can then be separated by chromatography on silica gel with a suitableeluent, such as methanol/methylene chloride.

[0095] In Scheme II, step C, amine (7) is sulfonylated in a manneranalogous to the procedure set forth in Scheme I, step F, to provide thesulfonamide (8).

[0096] In Scheme II, step C′, amine (7a) is sulfonylated in a manneranalogous to the procedure set forth in Scheme I, step F, to provide thesulfonamide (8a).

[0097] In Scheme II, step D, sulfonamide (8) is fluorinated in a manneranalogous to the procedure set forth in Scheme I, step G to provide thecompound of formula Ia.

[0098] In Scheme II, step D′, sulfonamide (8a) is fluorinated in amanner analogous to the procedure set forth in Scheme I, step G toprovide the compound of formula Ib.

[0099] In Scheme II, steps A or A′, compounds of formula Ia′ and Ib′ arenitrated under conditions well known in the art to provide the nitroderivatives of formulas Ic and Id. For example, the compound of formulaIa′ or Ib′ is combined with trifluoroacetic acid in a suitable organicsolvent mixture, such as methylene chloride and heptane. The mixture iscooled to about −5° C. and about 1.2 equivalents of 98/fuming nitricacid is added to the mixture. The reaction is then stirred at about −5°C. to 5° C. for about 3 to about 5 hours and then warmed to roomtemperature. The reaction mixture is then diluted with methylenechloride and water, and mixed for about 15 minutes. The aqueous phase isthen separated and extracted with methylene chloride. The organic phaseand organic extracts are combined, treated with water and aqueous base,such as 10% sodium hydroxide. The pH is adjusted to about 6.5 to about7.5 with saturated sodium carbonate. The mixture is stirred for about 10to 15 minutes and the organic layer is separated. The organic layer isthen concentrated under vacuum to provide p-nitro derivative of formulaIc or Id which is carried on directly to step F.

[0100] In Scheme III, steps B and B′, the compounds of formula Ic and Idare reduced under standard conditions to provide the amino derivativesof formulas Ie and If. For example, the crude p-nitro derivative offormula Ic or Id is dissolved in ethanol, treated with a suitablehydrogenation catalyst, such as palladium on is carbon and placed underhydrogen at a pressure sufficient to effect reduction of the p-nitroderivative to the p-amino derivative. The reaction is filtered and thefiltrate is concentrated under vacuum. The residue can then be purifiedusing standard techniques well known in the art, such as flashchromatography on silica gel with a suitable eluent, such as ethylacetate/hexanes to provide the amino derivatives of formulas Ie or If.

[0101] In Scheme IV, the compounds of formula Ie and If are amidatedunder conditions well known in the art to provide the compounds offormulas Ig and Ih wherein R^(15a) represents (1-6C)alkyl,fluoro(1-4C)alkyl, or phenyl which is unsubstituted or substituted byone or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy.For example, amide formation can be carried out using standard peptidecoupling procedures well known in the art, such as the azide method, themixed carbonic acid anhydride (isobutyl chloroformate) method, or thecarbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, orwater-soluble carbodiimide) method. Some of these methods, such as thecarbodiimide method, can be enhanced by adding 1-hydroxybenzotriazole.More specifically, for example, the amine of formula Ie or If isdissolved in a suitable organic solvent, such as methylene chlorideunder an atmosphere of nitrogen, and treated with an excess of asuitable organic base, such as triethylamine. The solution is cooled toabout 0° C. and treated with about 1.1 to about 1.5 equivalents of anacid chloride of formula ClCOR^(15a). After addition is complete, thereaction mixture is allowed to warm to room temperature and stirred forabout 8 to 16 hours. The reaction is then quenched with water and driedover anhydrous sodium sulfate, filtered, and concentrated under vacuumto provide the crude amide of formula Ig or Ih. This crude material canthen be purified by flash chromatography on silica gel with a suitableeluent, such as ethyl acetate/hexane.

[0102] In Scheme V, Steps A and A′, the compounds of formulas Ie and Ifare converted to the bromide derivatives of formulas Ii and Ij underconditions well known in the art, such as those disclosed by Wu andMosher, J. Org. Chem., 51, 1904 (1986).

[0103] In Scheme V, steps B and B′, the compound of formulas Ii and Ijare coupled with compound of structure (9) under standard Suzukicoupling conditions, which are well known in the art, to provide thecompounds of formulas Ik and Im. See Suzuki, A., Journal ofOrganometallic Chemistry, 576, 147-168 (1999), and Miyaura and Suzuki,Chemical Reviews, 95, 2457-2483 (1995) for examples of Suzuki-typecoupling reactions and conditions. Q in structure (9) represents aphenyl or heteroaromatic group which is unsubstituted or substituted byone or two of halogen; nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl;(2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ orNR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1C)alkylsulfonylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group is which is unsubstituted orsubstituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.

[0104] For example, compound of formula Ii or Ij is combined with about1.5 equivalents of compound (9), about 1.5 equivalents of potassiumcarbonate, and about 0.06 equivalents of tetrakis(triphenylphosphine)palladium(0) in a suitable solvent or solvent mixture, such asdioxane/water (3:1). The mixture is then heated at about 1 00° C. forabout 18 hours. The reaction is then cooled and the product is isolatedand purified using standard techniques and procedures, such asextraction techniques and chromatography. For example, the reactionmixture is extracted with a suitable organic solvent, such as ethylacetate, the organic extracts are combined, washed with water, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The crude material is then purified by chromatography on silica gel witha suitable eluent, such as hexane/ethyl acetate to provide purifiedcompound of formula Ik or Im.

[0105] In Scheme VI, step A the compound of formula lo is alkylatedunder conditions well known in the art to provide the compound offormula Ip. For example, the compound of formula lo is dissolved with asuitable organic solvent, such as acetone and treated with about 1.1 toabout 1.5 equivalents of a compound of formula R¹⁴(L_(a))_(n)-Lg wherein“Lg” refers to a suitable leaving group. Examples of suitable leavinggroups include, Cl, Br, and the like. About 1.1 to about 1.5 equivalentsof a suitable base, such as potassium carbonate are added and thereaction mixture is stirred at about 20° C. to about 40° C. for about 4to 14 hours. The reaction is then filtered and the filtratedconcentrated under vacuum to provide the crude compound of formula Ip.This crude material can then be purified by chromatography on silica gelwith a suitable eluent, such as methylene chloride/ethyl acetate.

[0106] In Scheme VI, step B the compound of formula Ip is converted tothe fluoro derivative of formula Iq in a manner analogous to theprocedure set forth in Scheme I, step G.

[0107] In Scheme VII, step A the compound of formula Io is alkylatedunder conditions well known in the art to provide the compound offormula Ir. For example, the compound of formula lo is dissolved in asuitable organic solvent, such as acetone and then treated with about1.1 to about 1.5 quivalents of a compound of formula NC(CH₂)_(t)-Lgwherein “Lg” refers to a suitable leaving group. Examples of suitableleaving groups include, Cl, Br, and the like. The solution is thentreated with about 1.1 to about 1.5 equivalents of a suitable base, suchas potassium carbonate and the reaction mixture is stirred at about 20°C. to about 40° C. for about 4 to 14 hours. The reaction is thenfiltered and the filtrated concentrated under vacuum to provide thecrude compound of formula Ir. This crude material can then be purifiedby chromatography on silica gel with a suitable eluent, such asmethylene chloride/ethyl acetate.

[0108] In Scheme VlI, step B compound of formula Ir is reduced understandard conditions to provide the compound of formula Is. For example,compound of formula Ir is dissolved in a suitable organic solvent, suchas THF and treated with a slight excess of a suitable reducing agent,such as borane-THF. The reaction mixture is then stirred at roomtemperature for about 4 to 14 hours and then quenched with methanol. Thereaction is then concentrated under vacuum and the residue purified bychromatography on silica gel with a suitable eluent, such as methylenechloride/ethyl acetate to provide the purified compound of formula Is.

[0109] In Scheme VII, step C, the compound of formula Is is sulfonylatedin a manner analogous to the procedure set forth in Scheme I, step F toprovide the compound of formula It.

[0110] In Scheme VII, step D, the compound of formula It is converted tothe fluoro derivative of formula Iu in a manner analogous to theprocedure set forth in Scheme I, step G.

[0111] In Scheme VII, step E the compound of formula Is is acylatedunder conditions well known in the art to provide the compound offormula Iv. For example, the compound of formula Is is dissolved in asuitable organic solvent, such as methylene chloride and cooled to about0° C. To this cooled solution is added about 1.5 equivalents of asuitable base, such as triethylamine and about 1.1 to about 1.5equivalents of a compound of formula R^(10a)CO-LG wherein “Lg” refers toa suitable leaving group. Examples of suitable leaving groups include,Cl, Br, and the like. The reaction mixture is allowed to warm to roomtemperature and stir for about 2 to 4 hours. It is then diluted withmethylene chloride, washed with water, the organic phase is dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum toprovide the crude compound of formula Iv. This crude material can thenbe purified by chromatography on silica gel with a suitable eluent, suchas hexanes/ethyl acetate.

[0112] In Scheme VII, step E, the compound of formula Iv is converted tothe fluoro derivative of formula Iu in a manner analogous to theprocedure set forth in Scheme I, step G.

[0113] The following examples further illustrate the invention andrepresent typical syntheses of the compounds of formula I as describedgenerally above. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. For example, seeInternational Patent Application Publications: WO 98/33496 publishedAug. 6, 1998; WO 99/43285 published Sep. 2, 1999; and WO 00/06159, WO00/06158, and WO 00/06148 all published Feb. 10, 2000. As used hereinthe term “Chromatotron®” (Harrison Research Inc., 840 Moana Court, PaloAlto, Calif. 94306) is recognized by is one of ordinary skill in the artas-an instrument which is used to perform centrifugal thin-layerchromatography. As used herein, the following terms have the meaningsindicated: “eq” refers to equivalents; “g” refers to grams; “mg” refersto milligrams; “kPa” refers to kilopascals; “L” refers to liters; “mL”refers to milliliters; “μL” refers to microliters; “mol” refers tomoles; “mmol” refers to millimoles; “psi” refers to pounds per squareinch; “min” refers to minutes; “h” or “hr” refers to hours; “° C.”refers to degrees Celsius; 37 TLC” refers to thin layer chromatography;“HPLC” refers to high performance liquid chromatography; “R_(f)” refersto retention factor; “R_(t)” refers to retention time; “δ” refers topart per million down-field from tetramethylsilane; “PTSA” refers top-toluenesulfonic acid: “THF” refers to tetrahydrofuran; “DMF” refers toN,N-dimethylformamide; “DMSO” refers to methyl sulfoxide; “LDA” refersto lithium diisopropylamide; “EtOAc” refers to ethyl acetate; “aq”refers to aqueous; “iPrOAc” refers to isopropyl acetate; “PdCl₂(dppf)”refers to [1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium (II);“Ph” refers to phenyl; “PPh₃” refers to triphenylphosphine; “DEAD”refers to diethyl azodicarboxylate; “methyl DAST” refers todimethylaminosulfur trifluoride, “DAST” refers to diethylaminosulfurtrifluoride, “DBU” refers to 1,8-diazabicyclo[5.4.0]undec-7-ene; “TFA”refers to trifluoroacetic acid; “DME” refers to dimethoxyethane; “9-BBN”refers 9-borabicyclo[3.3.1]nonane; and “RT” refers to room temperature.

EXAMPLE 1 Preparation ofTrans-[2-fluoro-2-(4-phenylphenyl)cyclohexyl](methylethyl)sulfonyl]amine

[0114]

Preparation of 1-(4-phenylphenyl)cyclohexan-1-ol

[0115]

[0116] Scheme I, step A: Into a flame dried 250 mL 3 neck flask that wasfitted with a thermometer and condenser, magnesium turnings (683 mg,28.1 mmol) were placed in anhydrous THF (15 mL). While stirring at roomtemperature under a nitrogen atmosphere, a small amount of4-diphenylbromide was added dropwise along with one iodine crystal anddibromoethane (0.01 mL). This mixture was stirred vigorously and heatedwith a heat gun. Grignard was initiated as foaming was observed frommetal turnings. The addition of 4-diphenylbromide was continueddropwise, keeping the temperature above 50° C. After the addition of4-diphenylbromide (8.00 g, 31.7 mmol, total), the reaction was heated atreflux for 45 minutes to insure complete Grignard formation. Thereaction was let cool to room temperature, and cyclohexanone (2.94 g,30.0 mmol) in THF (30 mL) was added dropwise. After addition, reactionwas refluxed for an additional 2 hours and then stirred overnight atroom temperature. In the morning, enough saturated ammonium chloride inwater was added to precipitate salts nicely and the organic layer wasdecanted off. The remaining salts were washed two times with ether andthe combined organic layers were concentrated under reduced vacuum. Theresulting semi-solid was taken into ethyl acetate, washed once withwater, dried over potassium carbonate, filtered, and concentrated underreduced vacuum to yield 8.41 g as a semi-solid. This material waspurified via silica gel chromatography employing the Water's Prep 2000and eluting with a solvent of hexane/ethyl acetate 19:1 to yield theintermediate title compound (4.93 g, 62%) as a white solid. Fd M.S.252.2 (M*).

[0117] Calculated for C₁₈H₂₀O: Theory: C 85.67, H 7.99. Found: C 86.35,H8.16

Preparation of 1-cyclohex-1-enyl-4-phenylbenzene

[0118]

[0119] Scheme I, step B: 1-(4-Phenylphenyl)cyclohexan-1-ol (6.30 g, 24.9mmol), p-toluenesulfonic acid (500 mg) and toluene (200 mL) were mixedtogether in a 500 mL 3 neck flask fitted with a thermometer and deanstark trap and stirred at reflux for 4 hours under a nitrogenatmosphere. The reaction was then let cool to room temperature andconcentrated under reduced vacuum. The resulting semi-solid was takeninto methylene chloride, washed once with water; dried over potassiumcarbonate, filtered, and concentrated under reduced vacuum to yield 6.13g as a solid. This material was purified via silica gel chromatographyemploying the Water's Prep 2000 and eluting with a solvent ofhexane/methylene chloride 9:1 to yield the intermediate title compound(5.80 g, 99%) as a white solid. Fd M.S. 234.2 (M*).

[0120] Calculated for C₁₈H₁₈: Theory: C 92.26, H 7.74. Found: C91.98,H7.37.

Preparation of 7-oxa-1-(4-phenylphenyl)bicyclo[4.1.0]heptane

[0121] Scheme I, step C: Into a 500 mL 3 neck flask fitted with astirrer, m-chloroperbenzoic acid (4.32 g, 3 equivalents) was addedportion wise to sodium fluoride (1.78 g, 5 equivalents) in methylenechloride (250 mL) while stirring at room temperature under a nitrogenatmosphere. After 0.5 hour at this temperature,1-cyclohex-1-enyl-4-phenylbenzene (2.00 g, 8.54 mmol) was added in oneportion and the mixture was stirred for an additional 2.5 hours at thistemperature. The mixture was then filtered and the filtrate was washedonce with 1.0 N NaOH, once with water, dried over potassium carbonate,filtered, and concentrated under reduced vacuum to yield 2.1 g as anoil. This material was purified via silica gel chromatography employingthe Water's Prep 2000 and eluting with a solvent of hexane/methylenechloride 7:3 to yield the intermediate title compound (1.37 g, 64%) as aclear oil. Fd M.S. 250.0 (M*).

[0122] IR (C—O stretch at 1190cm⁻¹).

Preparation of Trans-2-azido-1-(4-phenylphenyl)cyclohexan-1-ol (A) andTrans-2-azido-2-(4-phenylphenyl)cyclohexan-1-ol (B)

[0123]

[0124] Scheme I, step D: Into a 100 mL 3 neck flask fitted with astirrer and thermometer, sodium azide (1.66 g, 5.equivalents) in water(10 mL) was added. dropwise to a stirred solution of7-oxa-1-(4-phenylphenyl)bicyclo[4.1.0]heptane (1.35 g, 5.40 mmol) in DMF(40 mL) at room temperature. The reaction was then heated at 90° C.overnight. In the morning, the mixture was poured into water and theisomeric mix was extracted into ether. The organic layer was washed oncewith water, dried over potassium carbonate, filtered, and concentratedunder reduced vacuum to yield 1.31 g as a brown oil. This material wasused without further purification. Yield=Quantitative. Fd M.S. 292.9(M*). IR (C—N stretch at 2100cm⁻¹ ).

Preparation of Trans-2-amino-2-(4-phenylphenyl)cyclohexan-1-ol(Isomer 1) and Trans-2-amino-1-(4-phenylphenyl)cyclohexan-1-ol (isomer2)

[0125]

[0126] Scheme I, step E: Into a 100 mL 3 neck flask fitted with astirrer and thermometer, the mixture ofTrans-2-azido-1-(4-phenylphenyl)cyclohexan-1-ol (A) andTrans-2-azido-2-(4-phenylphenyl)cyclohexan-1-ol (1.30 g total) intoluene (20 mL) was added dropwise to a stirred solution of Red-AI® (5mL, excess, Aldrich) at room temperature under a nitrogen atmosphere.The reaction was stirred for 1.0 hour. The mixture was poured into waterand the desired isomeric mix was extracted into ethyl acetate. Theorganic layer was washed once with water, dried over potassiumcarbonate, filtered, and concentrated under reduced vacuum to yield 1.01g as an oil. The two spot material (by thin layer chromatography) waspurified via silica gel chromatography employing the Water's prep. 2000while eluting with a solvent of methylene chloride/methanol 9:1 to yieldthe intermediate title compound (335 mg, the top spot, isomer 2) as awhite solid. Ion spray M.S. 268.0 (M*+1).

Preparation ofTrans-[2-hydroxy-2-(4-phenylphenyl)cyclohexyl](methylethyl)sulfonyl]amine

[0127]

[0128] Scheme I, step F: In a 100 mL 3 neck flask fitted with a stirrerand thermometer, propanesulfonyl chloride (1.96 mg, 1.1 equivalents) wasadded dropwise to Trans-2-amino-1-(4-phenylphenyl)cyclohexan-1-ol (330mg, 1.24 mmol) and DBU (226 mg, 1.2 equivalents) in methylene chloride(150 mL) while stirring at 0° C. under a nitrogen atmosphere. Thereaction was allowed to warm to room temperature and stirred overnightat this temperature. In the morning, the reaction was diluted withmethylene chloride (50 mL) and the organic layer was washed two timeswith water, dried over sodium sulfate, filtered, and concentrated underreduced vacuum to yield 412 mg of a viscous oil. This material waspurified via silica gel chromatography employing the Chromatotron®,using a 4000 micron rotor and eluting with a solvent of methylenechloride/ethyl acetate 4:1 to yield the intermediate title compound (52mg, 11 %) as a white solid. Ion spray M.S. 372 (M*−1).

Preparation of Final Title Compound

[0129] Scheme I, step G: Into a 50 mL, 3 neck flask fitted with astirrer and thermometer,Trans-[2-hydroxy-2-(4-phenylphenyl)cyclohexyl][(methylethyl)sulfonyl]amine(35 mg, 0.1 mmol) in methylene chloride (5 mL) was added dropwise toDAST (0.01 mL, excess) in methylene chloride (50 mL) while stirring at−78° C. under a nitrogen atmosphere. The reaction was allowed to warm toroom temperature and diluted with methylene chloride (20 mL). Thisorganic layer was washed with water, dried over sodium sulfate,filtered, and concentrated under reduced vacuum to yield 35.1 mg as anoil. This material was purified via silica gel chromatography employingthe Chromatotron® and using a 1000 micron rotor while eluting with asolvent of methylene chloride to yield the final title compound (22.3mg, 59%) as a white foam. Ion spray M.S. 374 (M*−1).

[0130] Calculated for C₂, H₂₆ N O₂ S F: Theory: C 66.17, H 6.98, N 3.73.Found: C 66.61, H 6.86, N 3.76.

EXAMPLE 2 Preparation ofCis-[2-fluoro-2-(4-phenylphenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0131]

Preparation of 2-nitro-1-(4-phenylphenyl)cyclohexan-1-ol

[0132]

[0133] Scheme II, step A: Into a flame dried 500 mL 3 neck flask thatwas fitted with a thermometer and condenser, magnesium turnings (1.37 g,56.2 mmol) were placed anhydrous THF (20 mL). While stirring at roomtemperature under a nitrogen atmosphere, a small amount of4-diphenylbromide was added dropwise along with one iodine crystal anddibromoethane (0.01 mL). This mixture was stirred vigorously and heatedwith a heat gun. The Grignard was initiated as foaming was observed frommetal turnings. The addition of 4-diphenylbromide was continueddropwise, keeping the temperature above 50° C. After the addition of4-diphenylbromide (16.00 g, 63.4 mmol), the reaction was heated atreflux for 45 minutes to insure complete Grignard formation. Thereaction was allowed to cool to room temperature, and2-nitrocyclohexanone (8.58 g, 60 mmol) was added dropwise. Afteraddition, reaction was refluxed for an additional 2 hours and thenstirred overnight at room temperature. In the morning, enough saturatedammonium chloride in water was added to precipitate salts nicely and theorganic layer was decanted off. The remaining salts were washed twotimes with ether and the combined organic layers were concentrated underreduced vacuum. The resulting semi-solid was taken into ethyl acetate,washed once with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum to yield 18.41 g as an oil. Thismaterial was purified via silica gel chromatography employing theWater's Prep 2000 and eluting with a solvent of hexane/ethyl acetate19:1 to yield the intermediate title compound (4.01 g, 21 %) as a whitesolid. Fd M.S. 296.2 (M*−1).

Preparation of Cis-2-amino-1-(4-phenylphenyl)cyclohexan-1-ol (A) andTrans-2-amino-1-(4-phenylphenyl)cyclohexan-1-ol (B)

[0134]

[0135] Scheme II, step B: 2-Nitro-1-(4-phenylphenyl)cyclohexan-1-ol(1.75 g, 5.89 mmol) was combined with ethanol (200 mL) and palladium oncarbon (219 mg, 1.1 equivalents), and placed on the power shaker under ahydrogen atmosphere at 60 psi overnight. In the morning, the solutionwas filtered over a Celite® mat and the resulting filtrate wasconcentrated under reduced vacuum to yield 1.81 g as a viscous oil. Theresulting isomeric mixture can then be separated via silica gelchromatography employing the Water's prep. 2000 and a solvent ofmethylene chloride/methanol to provide isomer A and isomer B.

Preparation ofCis-[2-hydroxy-2-(4-phenylphenyl)cyclohexyl](methylethyl)sulfonyl]amine

[0136]

[0137] Scheme II, step C′: In a 100 mL 3 neck flask fitted with astirrer and thermometer, propanesulfonyl chloride (196 mg, 1.1equivalents) is added dropwise toCis-2-amino-1-(4phenylphenyl)cyclohexan-1-ol (330 mg, 1.24 mmol) and DBU(226 mg,. 1.2 equivalents) in methylene chloride (150 mL) while stirringat 0° C. under a nitrogen atmosphere. The reaction is allowed to warm toroom temperature and stirred overnight at this temperature. In themorning, reaction is diluted with methylene chloride (50 mL) and theorganic layer is washed two times with water, dried over sodium sulfate,filtered, and concentrated under reduced vacuum. This material can bepurified via silica gel chromatography employing the Chromatotron®,using a 4000 micron rotor to provide the intermediate title compound.

Preparation of Final Title Compound

[0138] Scheme II, step D′: Into a 50 mL, 3 neck flask fitted with astirrer and thermometer,Cis-[2-hydroxy-2-(4-phenylphenyl)cyclohexyl][(methylethyl)sulfonyl]amine(35 mg, 0.1 mmol) in methylene chloride (5 mL) is added dropwise to DAST(0.01 mL, excess) in methylene chloride (50 mL) while stirring at −78°C. under a nitrogen atmosphere. The reaction is allowed to warm to roomtemperature and diluted with methylene chloride (20 mL). This organiclayer is washed with water, dried over sodium sulfate, filtered, andconcentrated under reduced vacuum. This material is purified via silicagel chromatography employing the Chromatotrone® using a 1000 micronrotor to provide the final title compound.

EXAMPLE 3 Preparation ofTrans-[2-fluoro-2-(4-phenylphenyl)cyclopenyl][(methylethyl)sulfonyl]amine

[0139]

Preparation of 1-(4-phenylphenyl)cyclopentan-1-ol

[0140]

[0141] Scheme I, step A: Into a flame dried 500 mL 3n-flask that wasfitted with a thermometer and condenser, magnesium turnings (1.36 g,56.2 mmol) were placed in anhydrous THF (20 mL). While stirring at roomtemperature under a nitrogen atmosphere, a small amount of4-diphenylbromide was added dropwise along with one iodine crystal anddibromoethane (0.01 mL). This mixture was stirred vigorously and heatedwith a heat gun. Grignard was initiated as foaming was observed frommetal turnings. The addition of 4-diphenylbromide was continueddropwise, keeping the temperature above 50° C. After the addition of4-diphenylbromide (16.00 g, 63.4 mmol, total), the reaction was heatedat reflux for 45 minutes to insure complete Grignard formation. Thereaction was allowed cool to room temperature, cyclopentanone (5.05,60.0 mmol) was added dropwise. After addition, the reaction was heatedat reflux for an additional 2 hours and then stirred overnight at roomtemperature. In the morning, enough saturated ammonium chloride in waterwas added to precipitate salts nicely and the organic layer was decantedoff. The remaining salts were washed two times with ether and thecombined organic layers were concentrated under reduced vacuum. Theresulting semi-solid was taken into ethyl acetate, washed once withwater, dried over potassium carbonate, filtered, and concentrated underreduced vacuum to yield 16.50 g as an oil. This material was purifiedvia silica gel chromatography employing the Waters Prep 2000 and elutingwith a solvent of hexane/ethyl acetate 4:1 to yield the intermediatetitle compound (7.50 g, 50%) as a yellow solid. Fd M.S. 221 (M*−OH).

[0142] Calculated for C₁₇H₁₈O: Theory: C 85.67, H 7.61. Found: C 85.61,H 7.61.

Preparation of 1-cyclopent-1-enyl-4-phenylbenzene

[0143]

[0144] Scheme I, step B: 1-(4-Phenylphenyl)cyclopentan-1-ol (7.50 g,31.5 mmol), p-toluenesulfonic acid (650 mg) and toluene (200 mL) weremixed together in a 500 mL 3 neck flask fitted with a thermometer andDean Stark trap and stirred at reflux for 4 hours under a nitrogenatmosphere. The reaction was then allowed to cool to room temperatureand concentrated under reduced vacuum. The resulting semi-solid wastaken into methylene chloride, washed once with water, dried overpotassium carbonate, filtered, and concentrated under reduced vacuum toyield 7.73 g as a solid. This material was purified via silica gelchromatography employing′the Waters Prep 2000 and eluting with a solventof hexane/methylene chloride 4:1 to yield the intermediate titlecompound (4.71 g, 68%) as a white solid. Fd M.S. 220.1 (M*).

[0145] Calculated for C₁₇H₁₆: Theory: C 92.68, H 7.32. Found: C92.52,H7.18.

Preparation of 6-oxa-1-(4-phenylphenyl)bicyclo[3.1.0]hexane

[0146]

[0147] Scheme I, step C: Into a 1000 mL 3 neck flask fitted with astirrer, m-chloroperbenzoic acid (12.50 g, 3 equivalents) was addedportion wise to sodium fluoride (5.14 g, 5 equivalents) in methylenechloride (700 mL) while stirring at room temperature under a nitrogenatmosphere. After 0.5 hour at this temperature,1-cyclopent-1-enyl-4-phenylbenzene (5.44 g, 24.7 mmol) was added in oneportion and the mixture was stirred for an additional 2.5 hours at thistemperature. The mixture was then filtered and the filtrate was washedonce with 1.0 N NaOH, once with water, dried over potassium carbonate,filtered, and concentrated under reduced vacuum to yield 5.65 g as anoil. This material was purified via silica gel chromatography employingthe Water's Prep 2000 and eluting with a solvent of hexane/methylenechloride 7:3 to yield the intermediate title compound (3.50 g, 60%) as aslowly crystallizing oil. Fd M.S. 237.1 (M*+1).

[0148] 5 Calculated for C₁₇H₁₆O:

[0149] Theory: C 86.41, H 6.82.

[0150] Found: C 85.56, H 6.62.

Preparation of Trans-2-azido-1-(4-phenylphenyl)cyclopentan-1-ol (A) andTrans-2-azido-2-(4-phenylphenyl)cyclopentan-1-ol (B)

[0151]

[0152] Scheme I, step D: Into a 100 mL 3 neck flask fitted with astirrer and thermometer, sodium azide (1.66 g, 5 equivalents) in water(10 mL) is added dropwise to a stirred solution of6-oxa-1-(4-phenylphenyl)bicyclo[3.1.0]hexane. (1.35 g, 5.70 mmol) in DMF(40 mL) at room temperature. The reaction is then heated at 90° C.overnight. In the morning, the mixture is poured into water and theisomeric mixture is extracted into ether. The organic layer is washedonce with water, dried over potassium carbonate, and is concentratedunder reduced vacuum. This material can be used without furtherpurification.

Preparation of Trans-2-amino-2-(4-phenylphenyl)cyclorentan-1-ol(Isomer 1) and Trans-2-amino-1-(4-phenylphenyl)cyclopentan-1-ol (isomer2)

[0153]

[0154] Scheme I, step E: Into a 100 mL 3 neck flask fitted with astirrer and 2 5 thermometer,trans-2-azido-1-(4-phenylphenyl)cyclopentan-1-ol (A) andtrans-2-azido-2-(4-phenylphenyl)cyclopentan-1-ol (B) (1.35 g) in toluene(20 mL) is added dropwise to a stirred solution of 5 mL of Red-Al® atroom temperature under a nitrogen atmosphere. The reaction is stirredfor 1.0 hour. The mixture is then poured into water and the isomeric mixis extracted into ethyl acetate. The organic lay r is washed once withwater, dried over potassium carbonate, filtered, and concentrated underreduced vacuum. This crude material is purified and the isomers areseparated via silica gel chromatography employing the Water's prep. 2000to obtain each of the intermediate title compounds.

Preparation ofTrans-[2-hydroxy-2-(4-phenylphenyl)cyclopenyl][(methylethyl)sulfonyl]amine

[0155]

[0156] Scheme I, step F: In a 100 mL 3 neck flask fitted with a stirrerand thermometer propanesulfonyl chloride (196 mg, 1.1 equivalents) isadded dropwise to trans-2-amino-1-(4-phenylphenyl)cyclopentan-1-ol (330mg, 1.30 mmol) and DBU (226 mg, 1.2 equivalents) in methylene chloride(150 mL) while stirring at 0° C. under a nitrogen atmosphere. Thereaction is allowed to warm to room temperature and stirred overnight atthis temperature. In the morning, reaction is diluted with methylenechloride (50 mL) and the organic layer is washed two times with water,dried over sodium sulfate, filtered, and concentrated under reducedvacuum. This material is purified via silica gel chromatographyemploying the Chromatotron® using a 4000 micron rotor and eluting with asolvent of methylene chloride/ethyl acetate 4:1.

[0157]Cis-[2-hydroxy-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amineis prepared in an analogous manner.

Preparation of Final Title Compound

[0158] Scheme I, step G: Into a 50 mL 3 neck flask fitted with a stirrerand thermometer,trans-[2-hydroxy-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amine(35 mg, 0.1 mmol) in methylene chloride (5 mL) is added dropwise to DAST(0.01 mL, excess) in methylene chloride (50 mL) while stirring at −78°C. under a nitrogen atmosphere. The reaction is allowed to warm to roomtemperature and diluted with methylene chloride (20 mL). This organiclayer is washed with water, dried over sodium sulfate, filtered, andconcentrated under reduced vacuum. This material is purified via silicagel chromatography employing the Chromatotrone® and using a 1000 micronrotor and eluting with a solvent of methylene chloride to yield thefinal title compound.Cis-[2-fluoro-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amineis prepared in an analogous manner.

EXAMPLE 4 Preparation ofTrans-[(dimethylamino)sulfonyl][2-fluoro-2-(4-phenylphenyl)cyclohexyl]amine

[0159]

[0160] Scheme I, Step F: In a 500 mL 3 neck flask fitted with a stirrerand thermometer, dimethylsulfamoyl chloride (358 mg) is added dropwiseto trans-2-amino-1-(4-phenylphenyl)cyclohexan-1-ol (500 mg, intermediateprepared in example 1) and 380 mg of DBU (380 mg) in THF (125 mL) whilestirring at 0° C. under a nitrogen atmosphere. The reaction is allowedto warm to room temperature and stirred overnight at this temperature.In the morning, the reaction is concentrated under reduced vacuum. Thecrude residue is taken into ethyl acetate and the organic layer iswashed two times with water, dried over Na₂SO₄, filtered, andconcentrated under reduced vacuum. This material can be purified viasilica gel chromatography employing the Chromatotron® and using a 2000micron rotor while eluting with a solvent of hexane/ethyl acetate 3:1 toyield[(dimethylamino)sulfonyl][2-hydroxy-2-(4-phenylphenyl)cyclopentyl]amine.

Preparation of Final Title Compound

[0161] Scheme I, Step G: Into a 50 mL 3 neck flask fitted with a stirrerand thermometer,[(dimethylamino)sulfonyl][2-hydroxy-2-(4-phenylphenyl)cyclopentyl]amine(200 mg) in methylene chloride (10 mL) is added dropwise to DAST (0.08mL)in methylene chloride (10 mL) while stirring at −78° C. under anitrogen atmosphere. The reaction is allowed to warm to room temperatureand diluted with methylene chloride (25 mL). This organic layer iswashed with water, dried over Na₂SO₄, filtered, and concentrated underreduced vacuum. This crude material can be purified via silica gelchromatography employing the Chromatotrone® and using a 2000 micronrotor while eluting with a solvent of hexane/ethyl acetate 3:1 toprovide the final title compound.

EXAMPLE 5 Preparation ofTrans-(2-fluoro-2-phenylcyclohexyl)[(methylethyl)sulfonyl]amine

[0162]

Preparation of 1-phenylcyclohexan-1-ol

[0163]

[0164] Scheme I, step A: Into a flame dried 250 mL 3 neck flask fittedwith a thermometer and condenser, magnesium turnings (683 mg, 28.1 mmol)are placed in anhydrous THF (15 mL). While stirring at room temperatureunder a nitrogen atmosphere, a small amount of phenylbromide is addeddropwise along with one iodine crystal and dibromoethane (0.01 mL). Thismixture is stirred vigorously and heated with a heat gun. Grignard isinitiated when foaming is observed from metal turnings. The addition ofphenylbromide is continued dropwise, keeping the temperature above 50°C. After the addition of phenylbromide (31.7 mmol, total), the reactionis heated at reflux for about 45 minutes to insure complete Grignardformation. The reaction is then allowed to cool to room temperature, andcyclohexanone (2.94 g, 30.0 mmol) is added dropwise. After addition, thereaction is refluxed for an additional 2 hours and then stirredovernight at room temperature. In the morning, enough saturated ammoniumchloride in water is added to precipitate salts nicely and the organiclayer is decanted off. The remaining salts are washed two times withether and the combined organic layers are concentrated under reducedvacuum. The resulting semi-solid is taken into ethyl acetate, washedonce with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum. The crude material can then bepurified via silica gel chromatography employing s the Waters Prep 2000and eluting with a solvent of hexane/ethyl acetate 19:1 to yield theintermediate title compound

Preparation of cyclohex-1-enylbenzene

[0165]

[0166] Scheme I, step B: 1-phenylcyclohexan-1-ol (24.9 mmol),p-toluenesulfonic acid (500 mg) and toluene (200 mL) are mixed togetherin a 500 mL 3 neck flask fitted with a thermometer and Dean Stark trapand stirred at reflux for 4 hours under a nitrogen atmosphere. Thereaction is then allowed to cool to room temperature and concentratedunder reduced vacuum. The crude material is then taken into methylenechloride, washed once with water, dried over potassium carbonate,filtered, and concentrated under reduced vacuum. This material can thenbe purified via silica gel chromatography employing the Water's Prep2000 and eluting with a solvent of hexane/methylene chloride 9:1 toyield the intermediate title compound.

Preparation of 7-oxa-1-phenylbicyclo[4.1.0]heptane

[0167]

[0168] Scheme I, step C: Into a 500 mL 3 neck flask fitted with astirrer, m-chlorperbenzoic acid (4.32 g, 3 equivalents) is added portionwise to sodium fluoride (1.78 g, 5 equivalents) in methylene chloride(250 mL) while stirring at room temperature under a nitrogen atmosphere.After 0.5 hour at-this temperature, cyclohex-1-enylbenzene (8.54 mmol)is added in one portion and the mixture is stirred for an additional 2.5hours at this temperature. The mixture is then filtered and the filtrateis washed once with 1.0 N NaOH, once with water, dried over potassiumcarbonate, filtered, and concentrated under reduced vacuum. This crudematerial can be purified via silica gel chromatography employing theWaters Prep 2000 and eluting with a solvent of hexane/methylene chloride7:3 to yield the intermediate title compound.

Preparation of Trans-2-azido-1-phenylcyclohexan-1-ol (A) andTrans-2-azido-2-phenylcyclohexan-1-ol (B)

[0169]

[0170] Scheme I, step D: Into a 100 mL 3 neck flask fitted with astirrer and thermometer, sodium azide (1.66 g, 5 equivalents) in water(10mL) is added dropwise to a stirred solution of7-oxa-1-phenylbicyclo[4.1.0]heptane (5.40 mmol) in DMF (40 mL) at roomtemperature. The reaction is then heated at 90° C. overnight. In themorning, the mixture is poured into water and the isomeric mix isextracted into ether. The; organic layer is washed once with water,dried over potassium carbonate, filtered, and concentrated under reducedvacuum to yield material that can be used in the next step withoutfurther purification.

Preparation of Trans-2-amino-2-phenylcyclohexan-1-ol (Isomer 1) andTrans-2-amino-1-phenylcyclohexan-1-ol (isomer 2)

[0171]

[0172] Scheme I, step E: Into a 100 mL 3 neck flask fitted with astirrer and thermometer, the mixture ofTrans-2-azido-1-phenylcyclohexan-1-ol (A) andTrans-2-azido-2-phenylcyclohexan-1-ol (B) (1.30 g total) in toluene (mL)is added dropwise to a stirred solution of Red-Al® (5 mL, excess,Aldrich) at room temperature under a nitrogen atmosphere. The reactionis stirred for 1.0 hour. The mixture is poured into water and thedesired isomeric mix is extracted into ethyl acetate. The organic layeris washed once with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum. The crude material is purified viasilica gel chromatography employing the Water's prep. 2000 while elutingwith a solvent of methylene chloride/methanol 9:1 to yield theintermediate title compound as a white solid.

Preparation ofTrans-(2-hydroxy-2-phenylcyclohexyl)[(methylethyl)sulfonyl]amine

[0173]

[0174] Scheme I, step F: In a 100 mL 3 neck flask fitted with a stirrerand thermometer, propanesulfonyl chloride (1.96 mg, 1.1 equivalents) isadded dropwise to Trans-2-amino-1-phenylcyclohexan-1-ol (isomer 2) (1.24mmol) and DBU (226 mg, 1.2 equivalents) in methylene chloride (150 mL)while stirring at 0° C. under a nitrogen atmosphere. The reaction isallowed to warm to room temperature and stirred overnight at thistemperature. In the morning, the reaction is diluted with methylenechloride (50 mL) and the organic layer is washed two times with water,dried over sodium sulfate, filtered, and concentrated under reducedvacuum. This material is purified via silica gel chromatographyemploying the Chromatotrone®, using a 4000 micron rotor and eluting witha solvent of methylene chloride/ethyl acetate 4:1 to provide theintermediate title compound

Preparation of Final Title Compound

[0175] Scheme I, step G: Into a 50 mL, 3 neck flask fitted with astirrer and thermometer,Trans-(2-hydroxy-2-phenylcyclohexyl)[(methylethyl)sulfonyl]amine (0.1mmol) in methylene chloride (5 mL) is added dropwise to DAST (0.01 mL,excess) in methylene chloride (50 mL) while stirring at −78° C. under anitrogen atmosphere. The reaction is allowed to warm to room temperatureand diluted with methylene chloride (25 mL). This organic layer iswashed with water, dried over Na₂SO₄, filtered, and concentrated underreduced vacuum. This crude material can be purified via silica gelchromatography employing the Chromatotrone® and using a 2000 micronrotor while eluting with a solvent of hexane/ethyl acetate 3:1 toprovide the final title compound.

EXAMPLE 6 Preparation of[2-fluoro-2-(4-nitrophenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0176]

[0177] Scheme l1l, step A: To a round-bottom flask equipped with stirrod, thermocouple and nitrogen purge at 25° C., is chargedTrans-(2-fluoro-2-phenylcyclohexyl)[(methylethyl)sulfonyl]amine (0.0207mol), trifluoroacetic acid (15 mL), dichloromethane (1.2 mL) and heptane(8 mL). The reaction mixture is cooled to −5° C. and 98% fuming nitricacid (1.60 g, 0.0249 mol) is added dropwise. The reaction mixture isstirred at −5 to +5° C. for 3-5 hours and then warmed to 20-25°0 C. Thereaction is allowed to stir for an additional 3 to 6 hours.

[0178] The reaction mixture is then diluted with dichloromethane (20 mL)and deionized water (20 mL), and the mixture is transferred to asuitably sized 3-neck bottom outlet round-bottom flask. The mixture isstirred for 10-15 minutes. The aqueous phase is then separated,extracted with dichloromethane (1×20 mL), and the organic phases arecombined. To the organic phase is added water (15 mL), 10% NaOH (10 mL),and the pH is adjusted to 6.5-7.5 with saturated sodium carbonate. After10-15 minutes of stirring, the organic layer is separated andconcentrated under reduced pressure to provide the title compound.

EXAMPLE 7 Preparation of[2-fluoro-2-(4-aminophenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0179]

[0180] Scheme III, step B:[2-Fluoro2-(4-nitrophenyl)cyclohexyl][(methylethyl)sulfonyl]amine(prepared in example 6) is diluted with ethanol and was transferred to aParr bottle containing 1.25g of 5% Pd on C (rinsed in with 5 mL of THF)under nitrogen (total ethanol=45 mL). The reaction mixture is thenhydrogenated for 16-20 hours at 20-25° C. The reaction mixture is thenfiltered and the filtrate concentrated under vacuum. The residue canthen be purified by flash chromatography on silica gel with ethylacetate/hexanes to provide the final title compound.

EXAMPLE 8 Preparation of (35-difluorophenyl)N-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenyl]carboxamide

[0181]

[0182] Scheme IV: To a 0° C. solution of[2-fluoro-2-(4-aminophenyl)cyclohexyl][(methylethyl)sulfonyl]amine(0.0838 mol, from example 7) and triethylamine (9.75g, 13.4 mL, 0.0964mol) in CH₂Cl₂ (86 mL) is added 3,5-difluorobenzoyl chloride (16.3 g,0.0922 mol) dropwise over 30 min. After the addition is complete, thereaction mixture is allowed to stir at 20° C. for 1 hour. The reactionmixture is washed with deionized water (2×100 mL) and 0.1 N HCl (2×100mL). The organic phase is diluted with acetone (50 mL) to ensurecomplete dissolution of the product and the organic phase is washed withsaturated K₂CO₃ (100 mL), 0.1 N HCl (100 mL), dried (MgSO₄, 3 g),filtered and concentrated under vacuum. The residue can then be purifiedby flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane to provide the title compound.

EXAMPLE 9 Preparation of[2-fluoro-2-(4-bromophenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0183]

[0184] The title compound can be prepared in a manner analogous to theprocedure disclosed by Wu and Mosher, J. Org. Chem., 51, 1904 (1986).For example, a 50 mL, 3-neck flask is charged with[2-fluoro-2-(4-aminophenyl)cyclohexyl][(methylethyl)sulfonyl]amine (1.24mmoles, from example 7) followed by 6N HCl (4.9 mL, 29.3 mmoles). Thesolution is then cooled to 0° C. and is stirred for about 15 to 30minutes and a solution comprised of sodium nitrite (102 mg, 1.48 mmoles)in water (2 mL) is added dropwise to the reaction mixture. After about15 minutes, urea (97 mg, 1.6 mmoles) is added to destroy excess nitriteand the solution is stirred for an additional 30 minutes.

[0185] The mixture is then transferred to a 0° C. acetone solution (20mL) within another 50 mL 3-neck round-bottom flask. To this solution isadded a mixture of CuBr (265 mg, 1.85 mmoles) and LiBr (172 mg, 1.98moles) in two portions. The mixture is allowed to stir for an hour at 0°C. The reaction mixture is then concentrated under vacuum, diluted withethyl acetate and washed with water (2×50 mL), aqueous sodiumbicarbonate (1×50 mL) and brine (1×50 mL). The organic phase isseparated, dried over magnesium sulfate, filtered, and concentrated toprovide the title compound.

EXAMPLE 10 Preparation of{2-fluoro-2-[4-(4-(4-{2[(methylsulfonyl)amino]ethyl}phenyl)phenyl]cyclohexcyl}f[methylethyl)sulfonyl]-amine

[0186]

Preparation of (methylsulfonyl)(2-phenylethyl)amine

[0187]

[0188] To a 10° C. solution of phenethylamine (12.1 g, 0.100 mol) andtriethylamine (11.1 9, 0.110 mol) in CH₂Cl₂ (50 mL) was addedmethanesulfonyl chloride..(12.6 g, 0.110 mol) dropwise over 10 min. Thesolution was stirred at room temperature for 1.5 h and was then washedwith 1 N HCl (5×20 mL). The organic phase was directly concentrated toprovide the intermediate title compound,(methylsulfonyl)(2-phenylethyl)amine, (21.2 g, 93.3%) as an oil.

[0189]¹H NMR (CDCl₃, 300 MHz) δ 7.32 (m, 2H), 7.23 (m, 3H), 4.30 (br s,1H), 3.40 (t, 2H, J=3.9), 2.88 (t, 2H, J=4.2), 2.81 (s, 3H).

Preparation of [2-(4-iodophenyl)ethyl](methylsulfonyl)amine

[0190]

[0191] To a stirring room temperature solution of(methylsulfonyl)(2-phenylethyl)amine (205 g, 1.03 moles), water (200mL), 95% sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), wasadded iodine (111 g, 0.438 mol) and periodic acid (H₅IO₆, 45.6 g, 0.206mol). The reaction mixture was warmed to 70-75° C. for 3 h. The heat wasremoved and the dark violet reaction mixture was allowed to proceedovernight at room temperature. Potassium hydroxide pellets (85%, 143 g,2.16 moles) were added to neutralized the sulfuric acid and then enoughsaturated aqueous sodium sulfite was added to decolorize the mixture toafford a whit suspension. The suspension was cooled to 15° C. andfiltered. The filter cake was triturated thoroughly with water and wasthen dissolved in CH₂Cl₂ (1 L) and extracted with additional water(2×200 mL). The organic phase was concentrated under reduced pressure toprovide the intermediate title compound,[2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2%) as a whitepowder.

[0192]¹H NMR (CDCl₃, 300 MHz) δ7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1),4.37 (br t, 1H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t,2H, J=3.9).

Preparation of(tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide

[0193]

[0194] A room temperature solution of[2-(4-iodophenyl)ethyl](methylsulfonyl)amine (201 g, 0.618 mol),4-dimethylaminopyridine (3.8 g, 0.031 mol) and di-tert-butyl dicarbonate(162 g, 0.744 mol) in CH₂Cl₂ (1 L) was allowed to stir overnight. Thereaction mixture was washed with water (2×400 mL) and the organic phasewas concentrated to about 600 mL and hexanes (400 mL) was added. Thiscombined solution was washed again with water (400 mL) and wasconcentrated to a solid that was suspended in hexanes (600 mL) andfiltered. The collected solids were dried under reduced pressure toafford the intermediate title compound,(tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide(241.5 g, 91.5%) as a white solid.

[0195]¹H NMR (CDCl₃, 300 MHz) δ7.63 (d, 2H, J=7.8), 6.98 (d, 2H, J=7.8),3.88 (t, 2H, J=6.9), 3.10 (s, 3H), 2.88 (t, 2H, J=6.9), 1.51 (s, 9H).

Preparation of(tert-butoxy)-N-(methylsulfonyl)-N{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide

[0196]

[0197] To a degassed solution of(tert-butoxy)-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (128g, 0.300 mol), triethylamine (91.1 g, 0.900 mol), and1,1′-bis(diphenylphosphino) ferrocenedichloropalladium (II)-CH₂Cl₂complex (2.9 g, 0.0035 mol) in acetonitrile (600 mL) was addedpinacolborane (50 g, 0.391 mol) dropwise. The mixture was stirred at70-74 ° C. for 8 h and then was cooled to room temperature. The reactionmixture was concentrated to a fluid oil that was partitioned betweenMTBE (500 mL) and water (500 mL). The organic phase was separated andwashed with water (2×200 mL) and concentrated to a residue that waspartially dissolved with heptane (1 L). The heptane soluble fraction wasfiltered through Celite® 521 and concentrated to an oil (95 g). Theresidue was dissolved in acetone (600 mL) and heptane (600 mL) andfiltered through Celite® 521. The combined filtrates were concentratedto 95 g of a mixture of a 3:1 molar ratio (¹H NMR, 81.0% by weight) ofintermediate title compound,(tert-butoxy)-N-(methylsulfonyl)-N2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide,(60.3% potency corrected yield) and protio derivative.

[0198]¹H NMR (CDCl₃, 300 MHz) δ 7.75 (d, 2H, J=7.8), 7.23 (d, 2H,J=8.1), 3.87 (t, 2H, J=8.1), 2.99 (s, 3H), 2.90 (t, 2H, J=7.5), 1.53 (s,9H), 1.33 (s, 6H), 1.27 (s,6H).

Preparation of(methylsulfonyl{2-[4-(4,4,5,5tetramethyl(1,3,2-dioxaborolan-2-yl)phenyl]ethyl}amine

[0199]

[0200] To a 2 L flask charged with a stirring solution of(tert-butoxy)-N-(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide(98.7 g, 0.232 mol) in CH₂Cl₂ (500 mL) was added trifluoroacetic acid(82 mL, 121.4 g, 1.06 moles) dropwise from an addition funnel. Noexotherm was observed and the reaction solution was allowed to stir atroom temperature for 18 h.

[0201] HPLC analysis indicated 98% completion so the cooled (5° C.)reaction mixture was neutralized by the slow addition of 5 N NaOH (175mL). The pH of the aqueous phase was 10.5. The phases were separated andthe aqueous phase was extracted with CH₂Cl₂ (50 mL). The combined CH₂Cl₂phases were washed with brine (2×100 mL) and water (1×100 mL). TheCH₂Cl₂ phase was diluted with heptane (300 mL) and was concentratedunder reduced pressure to afford a suspension that was isolated byfiltration. The collected solids were washed with pentane (2×100 mL) anddried under vacuum to provide the intermediate title compound,(methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine,(69.0g, 91.4%) as a white powder. ¹H NMR (CDCl₃, 300 MHz) δ 7.77 (d, 2H,J=8.1), 7.22 (d, 2H, J=7.8), 4.26 (br t, 1H, J=6), 3.40 (q, 2H, J=6.9),2.89 (t, 2H, J=6.6), 2.82 (s, 3H), 1.34 (s, 12H).

Preparation of 4-{2-[(methylsulfonyl)amino]ethyl}benzene boronic Acid

[0202]

[0203](Methylsulfonyl){2-[4(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine(68.0 g, 0.209 mol) was placed into a 2 L flask and combined withacetone (600 mL), 1N ammonium acetate (600 mL), and NaIO₄ (168.1 g,0.786 mol). This mixture was stirred at room temperature overnight. Thereaction mixture was filtered to remove insoluble matter to affordfiltrate A. The collected solids were washed with acetone (2×100 mL) andthis filtrate was combined with filtrate A. The combined filtrates wereconcentrated under reduced pressure to 600 mL to afford a precipitatethat was recovered by filtration. The collected solids were air-dried togive 110 g of crude material. This crude material was suspended in water(100 mL) and 5N NaOH was added until the pH was 12.5. The resultingsuspension was filtered and the filtrate was treated with decolorizingcarbon (Darco 6-60). The mixture was filtered and the filtrate wasdiluted with 10N H₂SO₄ until the pH was 5.0 to precipitate theintermediate title compound. This precipitate was collected byfiltration and dried under reduced pressure to provide the intermediatetitle compound, 4-{2-[(methylsulfonyl)amino]ethyl}benzene boronic acid,(41.9 g, 82.5%) as a white 15 powder.

[0204]¹ ¹H NMR (acetone-d₆, 300 MHz) δ 7.82 (d, 2H, J=8.4), 7.27 (d, 2H,J=7.8), 7.11 (s, 2H), 6.03 (m, 1H), 3.36 (m, 2H), 2.91 (m, 2H), 2.84 (s,3H).

Preparation of Final Title Compound

[0205] Scheme V, step B: An aqueous solution of potassium formate isprepared in the following manner. To 15 mL of water is added KOH (85%flakes, 6.73 g, 0.102 mol), then 98% formic acid (4.70 g, 0.102 mol).Alternatively, one may use commercially available potassium formate. Tothis solution is then added K₂CO₃ (2.76 g, 0.0210 mol),4-{2-[(methylsulfonyl)amino]ethyl}benzene boronic acid (4.62 g, 0.190mol), 1-propanol (100 mL), and[2-fluoro-2-(4-bromophenyl)cyclohexyl][(methylethyl)sulfonyl]amine(0.200 mol, prepared in example 9). This mixture is deoxygenated viaabout three vacuum/N2-refill cycles. Palladium black (0.0215 g, 0.0002mol) is added and the mixture is again deoxygenated via threevacuum/N₂-refill cycles. The reaction flask is heated in a preheated oilbath at 88° C. and the mixture is stirred overnight.

[0206] The mixture is then diluted with ethyl acetate and filteredthrough Celite® to remove palladium. The mixture is concentrated underreduced pressure and the resulting residue is partitioned between ethylacetate and water. The organic phase is concentrated and the cruderesidue is purified by flash chromatography on silica gel with asuitable eluent, such as ethyl acetate/hexanes, or recrystallized from asuitable solvent mixture such as acetone/water to provide the purifiedfinal title compound.

EXAMPLE 11 Preparation of[2-fluoro-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amine

[0207]

Preparation of[(methylethyl)sulfonyl][2-(phenylmethoxy)cyclopentyl]amine

[0208]

[0209] Scheme IA, step A: In a 250 mL 3 neck flask fitted with a stirrerand thermometer, propanesulfonyl chloride (4.47 g, 1.2 eq) was addeddropwise to (1S,2S)-2-benzyloxycyclopentylamine (5.00 g, 10 mmol) andDBU (5.98 g, 1.5 eq) in CH₂Cl₂ (100 mL) while stirring at 0° C. under anitrogen atmosphere. The reaction was allowed to warm to roomtemperature and stirred overnight at this temperature. In the morning,the reaction was diluted with CH₂Cl₂ (100 mL) and the organic layer waswashed two times with H₂O, dried over Na₂SO₄, filtered, and concentratedunder reduced vacuum to yield 10.13 g as a viscous oil. This materialwas purified via silica gel chromatography employing the Water's Prep.2000 and eluting with a solvent of hexane/ethyl acetate 4:1 to yield theintermediate title compound (8.0 g, 95%) as a white solid. Ion sprayM.S. 296 (M*−1).

[0210] Analysis calculated for C₁₅H₂₃NO₃S: Theory: C 60.58, H 7.80, N4.71 Found: C 60.39, H 7.79, N 4.73

Preparation of (2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine

[0211]

[0212] Scheme IA, step B:[(Methylethyl)sulfonyl][2-(phenylmethoxy)cyclopentyl]amine (2.00 g, 6.72mmol), palladium on carbon (250 mg) and ethanol (50 mL) were combinedand placed on the power shaker under a hydrogen atmosphere at 60 psi'sovernight. In the morning, the solution was filtered over a Celitee® matand the resulting filtrate was concentrated under reduced vacuum toyield 1.50 g as a viscous oil. TLC showed material was very pure and wasused without further purification. Yield=Quantitative. Ion spray M.S.206 (M*−1).

[0213] Analysis calculated for C₈H₁₇NO₃S: Theory: C 46.35, H 8.26, N6.75

[0214] Found: C 46.27, H 7.97, N 6.70 .

Preparation of 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one

[0215]

[0216] Scheme IA, step C: Into a 250 mL single neck flask,(2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine (1.5 g, 7.24 mmol),pyridinium chlorochromate (2.34 g, 1.5 eq) and methylene chloride (100mL) were mixed together and stirred for 4 hours at room temperatureunder a nitrogen atmosphere. The solution was then filtered over aCelitee mat and the resulting filtrate was washed once with water, driedover potassium carbonate, and concentrated under reduced vacuum to yield1.31 g as an oil. This material was purified via silica gelchromatography employing the Chromatotrone® and using a 4000 micronrotor while eluting with a solvent of methylene chloride/ethyl acetate4:1 to yield the intermediate title compound (450 mg, 30%) as a slowlycrystallizing oil. Ion spray M.S. 204 (M*−1).

[0217] Analysis calculated for C₈H₁₅NO₃S: Theory: C 46.81, H 7.37, N6.82 Found: C 46.08, H 7.12, N 6.58.

Alternative Preparation of2{[(methylethyl)sulfonyl]amino}cyclopentan-1-one

[0218] Scheme IA, step C: Into a flame dried 500 mL 3 neck flask fittedwith a thermometer and magnetic stirrer, DMSO (6.16 mL) in methylenechloride (20 mL) was added dropwise to oxalyl chloride (3.80 mL) inmethylene chloride (100 mL) while stirring at −55° C. under a nitrogenatmosphere. After 2 minutes,(2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine (8.00 g, 38.6 mmol)in methylene chloride (45 mL) was added dropwise at this temperature andthe reaction was stirred for an additional 15 minutes. Triethylamine(25.5 mL) was is then added dropwise and the reaction was allowed towarm to room temperature. 180 mL of water was added at room temperatureand the layers were separated The organic layer was washed once withwater, dried over potassium carbonate, filtered, and concentrated underreduced vacuum to yield 7.83 g as a dark oil. This material was purifiedvia silica gel chromatography employing the Water's Prep. 2000 andeluting with a solvent of methylene chloride/ethyl acetate 9:1 toprovide the intermediate title compound (5.76 g, 73%) as a yellow oil.Ion Spray

[0219] M.S. 204.1 (M*−1). Calculated for C₈H₁₅NO₃S: Theory: C 46.81, H7.37, N 6.82. Found: C 46.56, H 7.32, N 6.77.

Preparation of[2-hydroxy-2-(4-phenylphenyl)cyclopentan][(methylethyl)sulfonyl]amine

[0220]

[0221] Scheme IA, step D: Into a flame dried 250 mL 3 neck flask that isfitted with a thermometer and condenser, are placed magnesium turnings(683 mg, 28.1 mmol) in anhydrous THF (15 mL). While stirring at roomtemperature under a nitrogen atmosphere, a small amount of4-bromo-dibenzene is added dropwise along with one iodine crystal anddibromoethane (0.01 mL). This mixture is stirred vigorously and heatedwith a heat gun until the Grignard is initiated. The addition of4-bromo-dibenzene is continued dropwise, keeping the temperature above50° C. After the addition of 4-bromo-dibenzene (8.00 g, 30 mmol, totalamount) is complete, the reaction is heated at reflux for 45 minutes toensure complete Grignard formation. The reaction is allowed to cool toroom temperature, and 2{[(methylethyl)sulfonyl]amino}cyclopentan-1-one(4.94 g, 24.1 mmol) is added dropwise. After addition is complete, thereaction is heated at reflux for an additional 2 hours and then stirredovernight at room temperature. In the morning, enough saturated ammoniumchloride in water is added to precipitate salts nicely and the organiclayer is decanted off. The remaining salts are washed two times withether and the combined organic layers are concentrated under reducedvacuum. The resulting material is taken into ethyl acetate, washed oncewith water, dried over potassium carbonate, filtered, and concentratedunder reduced vacuum. This isomeric mixture can be separated andpurified via silica gel chromatography employing the Water's Prep 2000.

Additional Preparation of[2-hydroxy-2-(4-Phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amine

[0222] Scheme IA, step D: Into a flame dried 250 mL 3 neck flask thatwas fitted with a thermometer and condenser, magnesium turnings (683 mg,28.1 mmol) were placed in 15 mL anhydrous THF. While stirring at roomtemperature under a nitrogen atmosphere, a small amount of4-bromo-dibenzene in THF (50 mL) was added dropwise along with oneiodine crystal and 0.01 mL of dibromoethane. This mixture was stirredvigorously and heated with a heat gun until the Grignard was initiatedas foaming was observed from metal turnings. The addition of4-bromo-dibenzene was continued dropwise, keeping the temperature above50° C. After the addition of 4-bromobiphenyl (8.00 g, 30 mmol), thereaction was heated at reflux for 45 minutes to insure complete Grignardformation. This reaction produced 60 mL of 0.032 M of di-bromobiphenylmagnesium bromide. The reaction was let cool to room temperature. Into aflame dried 100 mL 3 neck flask that was fitted with a thermometer andcondenser, 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one (500 mg,2.44 mmol) in THF (35 mL) was added dropwise to 10 mL of the abovesynthesized Grignard. After addition, reaction was refluxed for 2 hoursand then stirred overnight at room temperature. In the morning, enoughsaturated ammonium chloride in water was added to precipitate saltsnicely and the organic layer was decanted off. The remaining salts werewashed two times with ether and the combined organic layers wereconcentrated under reduced vacuum. The resulting material was taken intoethyl acetate, washed once with water, dried over potassium carbonate,filtered, and concentrated under reduced vacuum to yield 1.21 g of 2spot material as a yellow solid. This isomeric mixture was separated andpurified via silica gel chromatography employing the Water's Prep 2000while eluting with a solvent of methylene chloride/ethyl acetate 9:1 toprovide the intermediate title compound (130 mg, Cis) as a white solid(the top spot by TLC).

[0223] FD M:S. 360.1 (M*).

Preparation of Final Title Compound

[0224] Scheme IA, step E: Into a 50 mL 3 neck flask fitted with astirrer and thermometer,[2-hydroxy-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amine(35 mg, 0.1 mmol) in methylene chloride (5 mL) is added dropwise to 0.01mL DAST (0.01 mL, excess) in methylene chloride (50 mL) while stirringat −78° C. under a nitrogen atmosphere. The reaction is allowed to warmto room temperature and diluted with methylene chloride (20 mL). Thisorganic layer is washed with water, dried over sodium sulfate, filtered,and concentrated under reduced vacuum. The crude material is thenpurified via silica gel chromatography employing the Chromatotron® andusing a 1000 micron rotor to provide the purified final title compound.

Additional Preparation of Final Title Compound

[0225] Scheme IA, step E: Into a 50 3 neck flask fitted with a stirrerand thermometer,[2-hydroxy-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amine(108 mg, 0.1 mmol) in CH₂Cl₂ (5 mL) was added dropwise to 0.1 mL DAST inCH₂CL₂ (15 mL) while stirring at −78° C. under a nitrogen atmosphere.The reaction was allowed to warm to room temperature and diluted withCH₂Cl₂ (20 mL). The organic layer was washed with H₂O, dried overNa₂SO₄, filtered, and concentrated under reduced vacuum to yield 117 mgas an oil. This two spot material was purified via silica gelchromatography employing the Chromatotrone and using a 2000 micron rotorwhile eluting with a solvent of methylene chloride to provide the finaltitle compound (100 mg, quantitative yield) as an oil.

[0226] Ion Spray M.S. 360.2 (M*−1). Calculated for C₂₀H₂₄NO₂SF: Theory:C 66.46, H 6.69, N 3.88. Found: C66.76, H 6.55, N 4.02.

[0227] The compounds listed in Table 2 can be prepared by one ofordinary skill in the art from readily available reagents and startingmaterials in a manner analogous to the procedures disclosed herein. Thecompounds listed in Table 2 are preferred compounds in addition to thosedisclosed in the above examples. TABLE 2 Example Compound Structure 12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

EXAMPLE 44 Preparation of[2-(4-fluorophenyl-2-hydroxycyclopentyl][(methylethyl)sulfonyl]amine

[0228]

[0229] Scheme IA, step D: Into a flame dried 100 mL 3 neck flask thatwas fitted with a thermometer and condenser,2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one (1.10 g, 5.36 mmol) inTHF (25 mL) was added dropwise to 4-fluorophenylmagnesium bromide (3 mL,2M solution in diethyl ether) while stirring at room temperature under anitrogen atmosphere and keeping the temperature above 25° C. After theaddition was complete, the reaction was refluxed for 2 hours and thenstirred overnight at room temperature. In the morning, enough saturatedammonium chloride in water was added to precipitate the salts and theorganic layer was decanted off. The remaining salts were washed twotimes with ether and the combined organic layers were concentrated underreduced vacuum. The resulting material was taken into ethyl acetate,washed once with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum to yield 930 mg of a dark oil. Thisisomeric mixture was purified via silica gel chromatography employingthe Chromatotron® and using a 4000 micron rotor while eluting with asolvent of hexane/ethyl acetate 7:3 to provide the title compound (787mg, 49%) as an oil. Ion Spray M.S. 300.1 (M*−1).

[0230] Calculated for C₁₄H₂₀NO₃SF-1/2 H₂O: Theory: C, 54.16; H, 6.82; N,4.51. Found: C, 54.39; H, 6.61; N, 4.69.

EXAMPLE 45 Preparation of2-fluoro-2-(4-fluorophenyl)cyclopentyl][(methylethyl)sulfonyl]amine.

[0231]

[0232] Scheme IA, step E: Into a 50 mL 3 neck flask fitted with astirrer and thermometer,[2-(4-fluorophenyl)-2-hydroxycyclopentyl][(methylethyl)sulfonyl]amine(250 mg, 0.83 mmol) in CH₂Cl₂ (5 mL) was added dropwise to 0.1 mL DASTin CH₂CL₂ (10 mL) while stirring at −78° C. under a nitrogen atmosphere.The reaction was allowed to warm to room temperature and diluted withCH₂Cl₂ (20 mL). The organic layer was washed with H₂O, dried overNa₂SO₄, filtered, and concentrated under reduced vacuum to yield 196 mgas an orange oil. This two spot material was separated and. purified viasilica gel chromatography employing the Chromatotron® and using a 2000micron rotor while eluting with a solvent of methylene chloride toprovide the title compound (120 mg) as a viscous oil (top spot).

[0233] Ion Spray M.S. 302.2 (M*−1). Calculated for C₁₄H₁₉NO₂SF: Theory:C, 55.42; H, 6.31; N, 4.61. Found: C, 55.58; H, 5.92; N, 4.56.

EXAMPLE 46 Preparation oftrans-{2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amineandcis-}2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine

[0234]

[0235] Into a flame dried 500 mL 3 neck flask that was fitted with athermometer and condenser, magnesium turnings (899 mg, 38 mmol) wereplaced in anhydrous THF (15 mL). While stirring at room temperatureunder a nitrogen atmosphere, a small amount of 4-benzoxyphenyl bromidein THF (100 mL) was added dropwise along with one iodine crystal and0.01 mL of dibromoethane. This mixture was stirred vigorously and heatedwith a heat gun until the Grignard was initiated as foaming was observedfrom metal turnings. The addition of 4-benzoxyphenyl bromide wascontinued dropwise, keeping the temperature above 50° C. After theaddition of 4-benzoxyphenyl bromide (10.54 g, 40 mmol), the reaction washeated at reflux for 45 minutes to insure complete Grignard formation.The reaction was allowed to cool to room temperature.,2-{[(Methylethyl)sulfonyl]amino}cyclopentan-1-one (5.70 g, 27.8 mmol) inTHF (35 mL) was added dropwise. After addition was complete, thereaction was heated at reflux for 2 hours and then stirred overnight atroom temperature. Enough saturated ammonium chloride in water was thenadded to precipitate salts and the organic layer was decanted off. Theremaining salts were washed two times with ether and the combinedorganic layers were concentrated under reduced vacuum. The resultingmaterial was taken into ethyl acetate, washed once with water, driedover potassium carbonate, filtered, and concentrated under reducedvacuum to yield 11.51 g of a 2 spot material (TLC) as a dark oil. Thisisomeric mixture was separated and purified via silica gelchromatography employing the Water's Prep 2000 while eluting with agradient solvent of methylene chloride/ethyl acetate 19:1 to methylenechloride/ethyl acetate 9:1 to provide the trans isomer of title compound(1.35 g) as an oil (top spot). Ion Spray M.S. 388.2 (M*−1).

[0236] Continued elution afforded 250 mg of a mixture as an oil. IonSpray M.S. 388.2 (M*−1). Final elution afforded the cis isomer of thetitle compound (200 mg) as a slowly crystallizing oil (bottom spot). IonSpray M.S. 388.2 (M*−1).

[0237] Calculated for C₂₁H₂₇NO₄S: Theory: C, 64.76; H, 6.99; N, 3.60.Found: C, 64.77; H, 6.91; N, 3.56.

EXAMPLE 47 Preparation of[2-hydroxy-2-(4-hydroxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine

[0238]

[0239]cis/trans-{2-Hydroxy-2-[4-(phenylmethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine(1.44 mg, 3.70 mmol, prepared in example 46) was combined with 5%palladium on carbon (1.70 mg) in ethyl acetate (150 mL) and placed onthe power shaker under a hydrogen atmosphere at 45 psi's for 4 hours.The solution was filtered over a Celite® mat and the resulting filtratewas concentrated under reduced vacuum to yield 1.2 g as a white foam.This material was purified via silica gel chromatography employing theChromatotron® using a 4000 micron rotor while eluting with a gradientsolvent of methylene chloride/methanol 9:1 to methylenechloride/methanol 1:1 to provide the title compound (710 mg, 65%) as awhite foam. Yield=65%. Ion Spray M.S. 298.2 (M*−1).

[0240] Calculated for Cl₄H₂₁NO₄S: Theory: C, 56.17; H, 7.07; N, 4.68.Found: C, 55.94; H, 6.98; N, 4.51.

EXAMPLE 48 Preparation oftrans-(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amineandcis-(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine.

[0241]

[0242][2-Hydroxy-2-(4-hydroxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine(200 mg, 0.67 mmol), 3,5-difluorobenzyl bromide (153 mg, 1.1 eq) andpotassium carbonate (111 mg, 1.2 eq) were combined in acetone (20 mL)and stirred overnight at room temperature under a nitrogen atmosphere.The solution was then filtered and the filtrate was concentrated underreduced vacuum to yield 339 mg as an oil. This two spot material (TLC)was separated and purified via silica gel chromatography employing theChromatotron® and using a 4000 micron rotor while eluting with a solventof methylene chloride/ethyl acetate 9:1 to yield isomer #1 (17 mg) as awhite foam (top spot). Fd M.S. 425.2 (M*).

[0243] Continued elution afforded 203 mg of a mixture as an oil. Fd M.S.425.2 (M*). Calculated for C₂₁H₂₅NO₄SF₂-1/2 H₂O: Theory: C, 58.05; H,6.03; N, 3.22. Found: C, 58.23; H, 5.80; N, 3.07.

[0244] Final elution afforded isomer #2 (20.0 mg) as an oil (bottomspot). Fd M.S. 425.2 (M*).

EXAMPLE 49 Preparation of[2-hydroxy-2-(4-phenoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine

[0245]

[0246] Into a flame dried 250 mL 3 neck flask that was fitted with athermometer and condenser, and while stirring at room temperature undera nitrogen atmosphere, 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one(1.00 g, 4.9 mmol) in THF (40 mL) was added dropwise to 15 mL of 0.5 M4-phenoxyphenylmagnesium bromide. The addition of2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one was continueddropwise, keeping the temperature above 35° C. After the addition of2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one was complete, thereaction was stirred overnight at room temperature. Enough saturatedammonium chloride in water was then added to precipitate salts and theorganic layer was decanted off. The remaining salts were washed twotimes with ether and the combined organic layers were concentrated underreduced vacuum. The resulting semi-solid was taken into ethyl acetate,washed once with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum to yield 2.14 g of as a dark oil. Thismaterial was purified via silica gel chromatography employing the WatersPrep. 2000 while eluting with a solvent of hexane/ethyl acetate 7:3 toprovide the title compound (540 mg) as a white solid.

[0247] Ion spray M.S. 374.1 (M*−1). Calculated for C₂₀H₂₅NO₄S: Theory:C, 63.98; H, 6.71; N, 3.73. Found: C, 63.70; H, 6.77; N, 3.55.

EXAMPLE 50 Preparation oftrans-[2-fluoro-2-(4-phenoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amineandcis-[2-fluoro-2-(4-phenoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine

[0248]

[0249] Into a 50 mL 3 neck flask fitted with a stirrer and thermometer,[2-hydroxy-2-(4-phenoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine(500 mg, 1.30 mmol) in CH₂Cl₂ (5 mL) was added dropwise to 0.1 mL DASTin CH₂CL₂ (15 mL) while stirring at −78° C. under a nitrogen atmosphere.The reaction was allowed to warm to room temperature and diluted withCH₂Cl₂ (20 mL). This organic layer was washed with H₂O, dried overNa₂SO₄, filtered, and concentrated under reduced vacuum to yield 490 mgof a 2 spot material (TLC) as an oil. This material was separated andpurified via silica gel chromatography employing the Chromatotron® andusing a 4000 micron rotor while eluting with a solvent of hexane/ethylacetate 7:3 to provide the trans isomer of the title compound (97 mg) asa solid (top spot). Ion spray M.S. 376.4 (M*−1)

[0250] Calculated for C₂₀H₂₄NO₃SF: Theory: C, 63.64; H, 6.41; N, 3.71.Found: C, 63.82; H, 6.36; N, 3.66.

[0251] Continued elution afforded 271 mg of the 2 spot mixture as asemi-solid. Fd M.S. 376.4 (M*−1). Final elution afforded the cis isomerof the title compound (31 mg) as an oil (bottom spot). Ion spray M.S.376.4 (M*−1).

EXAMPLE 51 Preparation of[2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclopentyl][(methylethyl)sulfonyl]amine

[0252]

Preparation of2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile

[0253]

[0254][2-Hydroxy-2-(4-hydroxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine(650 mg, 2.17 mmol, prepared in example 47), bromoacetonitrile (292 mg,1.1 eq), and potassium carbonate (360 mg, 1.2 eq) were combined withacetone (40 mL) and stirred overnight at room temperature under anitrogen atmosphere. The solution was then filtered and the filtrate wasconcentrated under reduced vacuum to yield 694 mg as an oil. This twospot material was separated and purified via silica gel chromatographyemploying the Chromatotron® and using a 4000 micron rotor while elutingwith a solvent of methylene chloride/ethyl acetate 9:1 to yield theintermediate title compound (390 mg, 54%) as a white foam (top spot byTLC). Ion Spray M.S. 337.2 (M*−1)

[0255] Calculated for C₁₆H₂₂N₂O₄S: Theory: C, 56.79; H, 6.55; N, 8.28.Found: C, 56.51; H, 6.46; N, 8.24.

Preparation of{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine

[0256]

[0257] Into a 50 mL 3 neck flask with stirrer, borane-THF complex (2 mL,1M solution) was added syringe wise to2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile(125 mg, 0.37 mmol) in THF (10 mL) while stirring at room temperatureunder a nitrogen atmosphere. The reaction mixture was then stirredovernight. 3 mL of 1:1 THF/Methanol solution was then added by syringewith severe foaming. After the foaming subsided, the solution wasconcentrated under reduced vacuum to yield 85 mg as an oil. Thismaterial was purified via silica gel chromatography employing theChromatotron® and using a 2000 micron rotor while eluting with a solventof methylene chloride/ethyl acetate 9:1 to yield the intermediate titlecompound (35 mg) as an oil. Ion spray M.S. 341.4 (M*−1).

Alternative Preparation

[0258] Into a 100 mL, 3 neck flask with stirrer2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile(125 mg, 0.37 mmol)in toluene (10 mL) is added dropwise to Red-Al (3 mL,65% solution in toluene) while stirring at room temperature under anitrogen atmosphere. The reaction mixture is then stirred for two hoursat this temperature. The mixture is poured into water and the desiredmaterial is extracted with ethyl acetate. The organic layer is washedonce with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum to yield the crude product. Thismaterial is purified by silica gel chromatography with elution of asuitable solvent such as hexane/ethyl acetate to provide the puredesired material.

Preparation of Final Title Compound

[0259] In a 100 mL 3 neck flask fitted with a stirrer and thermometer,methanesulfonyl chloride (95 mg, 1.2 eq) is added dropwise to{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine(230 mg, 0.67 mmol) and DBU (153 mg, 1.5 eq) in CH₂Cl₂ (40 mL) whilestirring at 0° C. under a nitrogen atmosphere. The reaction is allowedto warm to room temperature and stirred overnight at this temperature.The reaction is then diluted with CH₂Cl₂ (50 mL) and the organic layeris washed two times with H₂O, dried over Na₂SO₄, filtered, andconcentrated under reduced vacuum to yield the product. This material isthen purified via silica gel chromatography employing the Chromatotron®and using 2000 micron rotor while eluting with a suitable eluent, suchas hexane/ethyl acetate to provide the final title compound.

EXAMPLE 52 Preparation of{2-hydroxy-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine

[0260]

[0261] The title compound is prepared in a manner analogous to theprocedure set forth in example 51 from 2-propanesulfonyl chloride and{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine.

EXAMPLE 53 Preparation ofN-{2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethyl}acetamide

[0262]

[0263] In a 100 mL 3 neck flask fitted with a stirrer and thermometer,acetyl chloride (63 mg, 1.2 eq) is added dropwise to{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine(230 mg, 0.67 mmol) and triethylamine (102 mg, 1.5 eq) in CH₂Cl₂ (40 mL)while stirring at 0° C. under a nitrogen atmosphere. The reaction isallowed to warm to room temperature and stirred for 2 hours. Thereaction is then diluted with CH₂Cl₂ (50 mL) and the organic layer iswashed two times with H₂O, dried over Na₂SO₄, filtered, and concentratedunder reduced vacuum to yield the product. This material is purified viasilica gel chromatography employing the Chromatotron® and using 2000micron rotor while eluting with a suitable eluent, such as hexanes/ethylacetate to provide the title compound.

EXAMPLE 54 Preparation of[2-fluoro-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclopentyl][(methylethyl)sulfonyl]amine

[0264]

[0265] Into a 50 mL 3 neck flask fitted with a stirrer and thermometer,[2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclopentyl][(methylethyl)sulfonyl]amine(150 mg, 0.36 mmol) in CH₂Cl₂ (5 mL) is added dropwise to 0.01 mL DASTin CH₂CL₂ (15 mL) while stirring at −78° C. under a nitrogen atmosphere.The reaction is allowed to warm to room temperature and diluted withCH₂Cl₂ (20 mL). This organic layer is washed with H₂O, dried overNa₂SO₄, filtered, and concentrated under reduced vacuum to yield theproduct. This material is purified via silica gel chromatographyemploying the Chromatotron® and using 2000 micron rotor while elutingwith a suitable eluent, such as hexanes/ethyl acetate to provide thefinal title compound.

EXAMPLE 55 Preparation of{2-fluoro-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine

[0266]

[0267] The title compound is prepared in a manner analogous to theprocedure set forth in example 54 from{2-hydroxy-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine.

EXAMPLE 56 Preparation ofN-{2-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethyl}acetamide

[0268]

[0269] The title compound is prepared in a manner analogous to theprocedure set forth in example 54 fromN-{2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethyl}acetamide.

EXAMPLE 57 Preparation of2-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile

[0270]

[0271] The title compound was prepared in a manner analogous to theprocedure set forth in example 54 from2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile(90 mg, 0.27 mmol) and DAST (0.01 mL) to yield the title compound (95mg) as an oil. This material was purified by silica gel chromatographyemploying the Chromatotron® and using a 1000 micron rotor while elutingwith a solvent methylene chloride/ethyl acetate 19:1 to yield the titlecompound (80 mg, 87%) as an oil. Ion Spray M.S. 339.1 (M*−1)

[0272] Calculated for C₁₆ H₂₁ N₂ O₃ S F: Theory: C, 56.45; H, 6.22; N,8.23. Found: C, 56.18; H, 6.06; N, 8.13.

EXAMPLE 58 Preparation of[2-(4-fluorophenyl)-2-hydroxycyclohexyl][(methylethyl)sulfonyl]amine

[0273]

Preparation of [(methylethyl)sulfonyl][2-(phenylmethoxy)cyclohexyl]amine

[0274]

[0275] In a 500 mL 3 neck flask fitted with a stirrer and thermometer,2-propanesulfonyl chloride (7.61 g, 1.1 eq) was added dropwise to(1S,2S)-benzoxycyclohexylamine (10.0 g, 0.05 mol) and DBU (8.89 g, 1.2eq) in CH₂Cl₂ (200 mL) while stirring at 0° C. under a nitrogenatmosphere. The reaction was allowed to warm to room temperature andstirred overnight at this temperature. In the morning, reaction wasdiluted with CH₂Cl₂ (200 mL) and the organic layer was washed two timeswith H₂O, dried over Na₂SO₄, filtered, and concentrated under reducedvacuum to yield 15.0 g as a viscous oil. This material was purified viasilica gel chromatography employing the Water's Prep. 2000 and elutingwith a solvent of methylene chloride to yield the intermediate titlecompound (12.46 g, 80%) as a slowly crystallizing oil. (FD) M.S. 311.3(M*).

Preparation of (2-hydroxycyclohexyl)[(methylethyl)sulfonyl]amine

[0276]

[0277] [(Methylethyl)sulfonyl][2-(phenylmethoxy)cyclohexyl]amine (11.41g, 36.6 mmol) and 10% palladium on carbon (1.40 g) were combined inethanol (300 mL) and placed on the power shaker under a hydrogenatmosphere at 60 psi's overnight. The solution was then filtered over aCelite® mat and the resulting filtrate was concentrated under reducedvacuum to yield the intermediate title compound (6.78 g, 84%) as a whitesolid. Ion Spray M.S. 222.1 (M*+1).

[0278] Calculated for C₉H₁₉NO₃S: Theory: C, 48.84; H, 8.65; N, 6.32.Found: C, 49.10; H, 8.84; N, 6.42.

Preparation of 2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one

[0279]

[0280] Into a 500 mL single neck flask(2-hydroxycyclohexyl)[(methylethyl)sulfonyl]amine (6.78 g, 30.6 mmol)was combined with pyridinium chlorochromate (7.92 g, 1.2 eq) inmethylene chloride (300 mL) and stirred at room temperature under anitrogen atmosphere for 4 hours. The solution was then filtered over aCelite® mat and the organic layer was washed once with water, dried overpotassium carbonate, filtered, and concentrated under reduced vacuum toyield 13.42 g as a dark oil. This material was purified via silica gelchromatography employing the Water's Prep. 2000 and eluting with asolvent of methylene chloride/ethyl acetate 19:1 to yield theintermediate title compound (3.95 g, 59%). as a white solid. Ion SprayM.S. 218 (M*−1).

[0281] Calculated for C₉H₁₇NO₃S: Theory: C, 49.29; H, 7.81; N, 6.39.Found: C, 49.25; H, 7.58; N, 6.32.

Alternative Preparation of2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one

[0282] Into a flame dried 250 mL 3 neck flask fitted with a thermometerand magnetic stirrer, DMSO (2.61 mL) in methylene chloride (10 mL) wasadded dropwise to oxalyl chloride (1.60 mL) in methylene chloride (50mL) while stirring at −55° C. under a nitrogen atmosphere. After 2minutes, (2-hydroxycyclohexyl)[(methylethyl)sulfonyl]amine (3.60 g, 16.3mmol) in methylene chloride (10 mL) was added dropwise at thistemperature and the reaction was stirred for an additional 15 minutes.Triethylamine (10.8 mL) was then added dropwise and the reaction wasallowed to warm to room temperature. Water (76 mL) was added at roomtemperature and the layers were separated. The organic layer was washedonce with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum to yield 3.90 g as an orange solid.This material was purified via silica gel chromatography employing theWater's Prep. 2000 and eluting with a solvent of methylenechloride/ethyl acetate 19:1 to yield the intermediate title compound(2.94 g, 82%) as a white solid. FD M.S. 219.2 (M*).

[0283] Calculated for C₉H₁₇NO₃S: Theory: C, 49.29; H, 7.81; N, 6.39.Found: C, 49.18; H, 7.84; N, 6.39.

Preparation of Final Title Compound

[0284] Into a flame dried 100 mL 3 neck flask that was fitted with athermometer and condenser, and while stirring at room temperature undera nitrogen atmosphere, 2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one(1.18 g, 13.2 mmol) in THF (25 mL) was added dropwise to4-fluorophenylmagnesium bromide (3 mL, 17.5 mmol, 2 M solution). Theaddition of 2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one wascontinued dropwise, keeping the temperature above 35 C. After theaddition of 2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one, thereaction was stirred overnight at room temperature. Enough saturatedammonium chloride in water was then added to precipitate salts and theorganic layer was decanted off. The remaining salts were washed twotimes with ether and the combined organic layers were concentrated underreduced vacuum. The resulting semi-solid was taken into ethyl acetate,washed once with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum to yield 1.30 g as a semi-solid. Thismaterial was purified via silica gel chromatography employing theChromatotron® while using a 4000 micron rotor and eluting with agradient solvent of methylene chloride to methylene chloride/ethylacetate 9:1 to yield the final title compound (430 mg, 25%) as a slowlycrystallizing oil. Ion Spray M.S. 314.0 (M*−1).

[0285] Calculated for C₁₅H₂₂ NO₃ SF-1/2H₂O: Theory: C, 55.52; H, 7.14;N, 4.32. Found: C, 55.78; H, 6.88; N, 4.45.

EXAMPLE 59 Preparation oftrans-[2-fluoro-2-(4-fluorophenyl)cyclohexyl][(methylethyl)sulfonyl]amineandcis-[-2-fluoro-2-(4-fluorophenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0286]

[0287] Into a 50 mL 3 neck flask fitted with a stirrer and thermometer,[2-(4-fluorophenyl)-2-hydroxycyclohexyl][(methylethyl)sulfonyl]amine(200 mg, 0.63 mmol) in CH₂Cl₂ (5 mL) was added dropwise to 0.1 mL DASTin CH₂CL₂ (15 mL) while stirring at −78° C. under a nitrogen atmosphere.The reaction was allowed to warm to room temperature and diluted withCH₂Cl₂ (20 mL). This organic layer was washed with H₂O, dried overNa₂SO₄, filtered, and concentrated under reduced vacuum to yield 220 mgof a 2 spot material (by TLC) as an oil. This material was separated andpurified via silica gel chromatography employing the Chromatotron® andusing a 4000 micron rotor while eluting with a solvent of methylenechloride/ethyl acetate 19:1 to yield the trans title compound (80 mg) asa white foam (top spot by TLC). Ion spray M.S. 316.1 (M*−1).

[0288] Calculated for C₁₅ H₂₁ N O₂ S F₂: Theory: C, 56.76; H, 6.71; N,4.41. Found: C, 56.43; H, 6.69; N, 4.21.

[0289] Continued elution afforded 62 mg of the 2 spot mixture as an oil.Fd M.S. 316.1 (M*−1).

[0290] Calculated for C₁₅ H₂₁ N O₂ S F₂: Theory: C, 56.76; H, 6.71; N,4.41. Found: C, 57.46; H, 7.09; N, 4.35.

[0291] Final elution afforded the cis title compound (26 mg) as a whitesolid (bottom spot by TLC). Ion spray M.S. 316.1 (M*−1).

[0292] Calculated for C₁₅ H₂₁ N O₂ S F₂: Theory: C, 56.76; H, 6.71; N,4.41. Found: C, 56.60; H, 6.89; N, 4.35.

EXAMPLE 60 Preparation ofcis-[2-hydroxy-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amineandtrans-[2-hydroxy-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine.

[0293]

[0294] Into a flame dried 250 mL 3 neck flask that was fitted with athermometer and condenser, and while stirring at room temperature undera nitrogen atmosphere, 2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one(2.90 g, 13.2 mmol) in THF (50 mL) was added dropwise to4-methoxyphenylmagnesium bromide (35 mL, 17.5 mmol, 0.5 M solution). Theaddition of 2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one wascontinued dropwise, keeping the temperature above 35° C. After theaddition of 2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one, thereaction was stirred overnight at room temperature. Enough saturatedammonium chloride in water was added to precipitate salts and theorganic layer was decanted off. The remaining salts were washed twotimes with ether and the combined organic layers were concentrated underreduced vacuum. The resulting semi-solid was taken into ethyl acetate,washed once with water, dried over potassium carbonate and concentratedunder reduced vacuum to yield 3.02 g as a dark semi-solid. This materialwas purified via silica gel chromatography employing the Water's Prep2000 and eluting with a gradient solvent of methylene chloride/ethylacetate 19:1 to methylene chloride/ethyl acetate 9:1 to yield a mixtureof the cis and trans isomers of the title compound (1.03 g) as a whitesolid Ion Spray M.S. 326.1 (M*−1).

[0295] Calculated for C₁₆H₂₅ NO₄S-1/2H₂O: Theory: C, 57.11; H, 7.74; N,4.16. Found: C, 57.69; H, 7.49; N, 3.76.

[0296] This isomeric two spot material (400 mg) was further separatedvia silica gel chromatography using the Chromatotron® and employing a4000 micron plate and eluting with a solvent of hexane/ethyl acetate 7:3to yield the title compound (40 mg) as a white solid (top spot by TLC,cis isomer). Ion Spray M.S. 326.1 (M*−1).

[0297] Continued elution afforded the title compound (10 mg) as a whitesolid (bottom spot by TLC, trans isomer). Ion Spray M.S. 326.1 (M*−1)

EXAMPLE 61 Preparation oftrans-{2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amineandcis-{2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine

[0298]

[0299] Into a flame dried 250 mL 3 neck flask that was fitted with athermometer and condenser, magnesium turnings (370 mg, 15.2 mmol) wasplaced in 10 mL anhydrous THF. While stirring at room temperature undera nitrogen atmosphere, a small amount of 4-benzoxyphenyl bromide wasadded dropwise along with one iodine crystal and 0.01 mL ofdibromoethane. This mixture was stirred vigorously and heated with aheat gun. Grignard was initiated as foaming was observed from metalturnings. The addition of 4-benzoxyphenyl bromide was continueddropwise, keeping the temperature, above 50° C. After the addition of4-benzoxyphenyl bromide (4.00 g, 15.2 mmol), the reaction was heated atreflux for 45 minutes to insure complete Grignard formation. Thereaction was allowed to cool to room temperature, and2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one (1.50 g, 6.84 mmol) inTHF (50 mL) was added dropwise. After addition, the reaction wasrefluxed for an additional 2 hours and then stirred overnight at roomtemperature. Enough saturated ammonium chloride in water was then addedto precipitate salts and the organic layer was decanted off. Theremaining salts were washed two times is with ether and the combinedorganic layers were concentrated under reduced vacuum. The resultingsemi-solid was taken into ethyl acetate, washed once with water, driedover potassium carbonate, filtered, and concentrated under reducedvacuum to yield 4.73 g as a dark oil. This material was purified viasilica gel chromatography employing the Water's Prep 2000 and elutingwith a gradient solvent of hexane/ethyl acetate 4:1 to hexane/ethylacetate 1:1 to provide a cis/trans mixture of the title compound (1.21g) as an oil. Ion Spray M.S. 402.1 (M*−1). This isomeric 2 spot material(1 g) was separated via silica gel chromatography employing the Water'sPrep 2000 and eluting with a gradient solvent of hexane/ethyl acetate4:1 to hexane/ethyl acetate 1:1 to provide the cis isomer of the titlecompound (130 mg, top spot by TLC) as a slowly crystallizing oil. IonSpray M.S. 402.1 (M*−1).

[0300] Calculated for C₂₂H₂₉NO₄S-1/2H₂O: Theory: C, 64.00; H, 7.33; N,3.40. Found: C, 64.26; H, 6.93; N, 2.91.

[0301] Further elution yielded the trans isomer of the title compound(70 mg, bottom spot by TLC) as a slowly crystallizing oil. Ion SprayM.S. 402.1 (M*−1).

[0302] Calculated for C₂₂H₂₉ NO₄ S: Theory: C, 65.48; H, 7.24; N, 3.47.Found: C, 64.84; H, 6.99; N, 2.90.

EXAMPLE 62 Preparation oftrans-[2-hydroxy-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amineandcis-[2-hydroxy-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0303]

[0304] The title compounds were prepared in a manner analogous to theprocedure set forth in Example 60 from 4-phenoxyphenylmagnesium bromide(17 mL, 1.1 eq., 0.5 M solution) and2-{[(methylethyl)sulfonyl]amino}cyclohexan-1-one (1.70 g, 7.8 mmol) toprovide a cis/trans mixture of the title compound (3.24 g) as a darksemi-solid. This material was separated and purified via silica gelchromatography employing the Waters Prep. 2000 while eluting with asolvent of hexane/ethyl acetate 3:2 to yield the cis isomer of the titlecompound (70 mg, top spot by TLC) as a white solid. Ion spray M.S. 388.1(M*−1).

[0305] Calculated for C₂₁ H₂₇ N O₄ S: Theory: C, 64.76; H, 6.99; N,3.60. Found: C, 63.98; H, 7.07; N, 3.42.

[0306] Continued elution afforded the trans isomer of the title compound(91 mg, bottom spot by TLC) as a semi-solid. Fd M.S. 388.2 (M*−1).

[0307] Calculated for C₂, H₂₇ N O₄ S-1/2 H₂O: Theory: C, 63.23; H, 7.08;N, 3.52. Found: C, 62.81; H, 6.93; N, 3.29.

EXAMPLE 63 Preparation oftrans-[2-fluoro-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amineandcis-[2-fluoro-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine.

[0308]

[0309] The title compounds were prepared in a manner analogous to theprocedure set forth in Example 59 from a cis/trans mixture of[2-hydroxy-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine(200 mg, 0.61 mmol) to provide a cis/trans mixture of the titlecompounds (220 mg) as an oil. This material was separated and purifiedvia silica gel chromatography employing the Chromatotron® and using a4000 micron rotor while eluting with a solvent of methylene chloride toyield the trans isomer of the,title compound (120 mg, top spot by TLC)as an oil. Ion spray M.S. 309.1 (M*-Fluorine).

[0310] Calculated for C₁₆ H₂₄ N O₃ S F: Theory: C, 58.34; H, 7.34; N,4.25. Found: C, 57.69; H, 7.39; N, 4.19.

[0311] Continued elution afforded a cis/trans mixture (60 mg) as an oil.Fd M.S. 329.4 (M*). Final elution afforded the cis isomer of the titlecompound (13 mg, bottom spot by TLC) as a semi solid material. Ion sprayM.S. 309.1 (M*-Fluorine).

[0312] Calculated for C₁₆ H₂₄ N O₃ S F: Theory: C, 58.34; H, 7.34; N,4.25. Found: C, 58.76; H, 7.73; N, 3.92.

EXAMPLE 64 Preparation oftrans-{2-fluoro-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amineandcis-{2-fluoro-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine

[0313]

[0314] The title compounds were prepared in a manner analogous to theprocedure set forth in Example 59 from a cis/trans mixture oftrans-{2-hydroxy-2-[4-phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine(2.20 g, 5.45 mmol) to yield a cis/trans mixture of the title compounds(2.45 g) as an oil. This material was separated and purified in 3 lotsvia silica gel chromatography employing the Chromatotron® and using a4000 micron rotor while eluting with a solvent of hexane/tetrahydrofuran4:1 to yield the trans isomer of the title compound (1.31 g, top spot byTLC) as an oil. Ion spray M.S. 404.1 (M*−1).

[0315] Continued elution afforded the cis isomer of the title compound(80 mg, bottom spot by TLC) as a viscous oil. Ion spray M.S. 404.1(M*−1).

[0316] Calculated for C₂₂ H₂₈ N O₃ S F-1/2 H₂O: Theory: C, 63.76; H,7.05; N, 3.38. Found: C, 63.80; H, 7.30; N, 3.61.

EXAMPLE 65 Preparation oftrans-[2-fluoro-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amineandcis-[2-fluoro-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine.

[0317]

[0318] The title compounds are prepared in a manner analogous to theprocedure set forth in Example 59 from[2-hydroxy-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine toprovide a cis/trans mixture of the title compounds (212 mg) as an oil.This material was separated and purified via silica gel chromatographyemploying the Chromatotron® and using a 4000 micron rotor while elutingwith a solvent of hexane/ethyl acetate 4:1 to yield the trans isomer ofthe title compound (35 mg, top spot by TLC) as an oil. Ion spray M.S.390.1 (M*−1).

[0319] Calculated for C₂₁ H₂₆ N O₃ S F: Theory: C, 64.43; H, 6.70; N,3.58. Found: C, 64.26; H, 6.64; N, 3.50.

[0320] Continued elution afforded a cis/trans mixture (133 mg) as anoil. Fd M.S. 390.1 (M*−1). Final elution afforded the cis isomer of thetitle compound (20 mg, bottom spot by TLC) as an oil. Ion spray M.S.390.1 (M*−1).

EXAMPLE 66 Preparation of[2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0321]

[0322]{2-Hydroxy-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine(5.00 g, 12.8 mmol) was combined with 5% palladium on carbon in ethylacetate (200 mL) mixed together and placed on the power shaker under ahydrogen atmosphere at 45 psi's overnight. The solution was filteredover a Celite® mat and the resulting filtrate was concentrated underreduced vacuum to yield 4.1 g as a white solid. This material waspurified via silica gel chromatography employing the Water's prep. 2000while eluting with a solvent of methylene chloride/methanol 9:1 toprovide the title compound (3.75 g, 94%) as a white solid. Ion SprayM.S. 312.1 (M*−1).

[0323] Calculated for C₁₅H₂₃NO₄S: Theory: C, 57.48; H, 7.40; N, 4.47.Found: C, 57.11; H, 7.40; N, 4.65.

EXAMPLE 67 Preparation ofcis-[2-fluoro-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amineandtrans-[2-fluoro-2-(4hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0324]

[0325] The title compounds are prepared in a manner analogous to theprocedure set forth in Example 59 from[2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine(250 mg, 0.83 mmol) to provide 262 mg of a 2 spot material as a yellowsolid. This material was separated and purified via silica gelchromatography employing the Chromatotron® and using a 4000 micron rotorwhile eluting with a solvent of hexane/ethyl acetate 3:2 to yield thetrans isomer of the title compound (110 mg, top spot by TLC) as a whitesolid. Ion spray M.S. 296.1 (M*−19 fluorine).

[0326] Calculated for C₁₅ H22 N O₃ S F: Theory: C, 57.12; H, 7.03; N,4.44. Found: C, 57.08; H, 7.08; N, 4.47.

[0327] Continued elution afforded 100 mg of a cis/trans mixture of thetitle compound as an oil. Fd M.S. 315.1.1 (M*).

EXAMPLE 68 Preparation of{2-hydroxy-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine

[0328]

Preparation of2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethanenitrile

[0329]

[0330][2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine(3.40 g, 10.9 mmol), bromoacetonitrile (1.44 g, 1.1 eq) and potassiumcarbonate (1.80 g, 1.2 eq) were combined in acetone (20 mL) and stirredovernight at room temperature under a nitrogen atmosphere. The solutionwas then filtered and the filtrate was concentrated under reduced vacuumto yield 3.71 g as a brown oil. This material was purified via silicagel chromatography employing the Water's Prep. 2000 while eluting with asolvent of hexane/ethyl acetate 3:2 to yield the intermediate titlecompound (2.52 g, 67%) as a tan solid. Ion spray M.S. 351.2 (M*−1).

[0331] Calculated for Cl₇ H₂₄ N_(2 O) ₄ S: Theory: C, 57.93; H, 6.86; N,7.95. Found: C, 57.61; H, 6.84; N, 8.12.

Preparation of{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclohexyl}[(methylethyl)sulfonyl]amine

[0332]

[0333] Into a 100 mL, 3 neck flask with stirrer,2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethanenitrile(400 mg) in THF-toluene 1:1 (30 ml) was added dropwise to Red-Al® (3 mL,65% solution in toluene) while stirring at room temperature under anitrogen atmosphere. The reaction mixture was then stirred for two hoursat this temperature. The mixture was poured into water and the desiredmaterial was extracted with ethyl acetate. The organic layer was washedonce with water, dried over potassium carbonate, filtered, andconcentrated under reduced vacuum to yield the intermediate titlecompound (478 mg, 89%) as a white foam. This material was used withoutfurther purification. Ion spray M.S. 355.2 (M*−1).

[0334] Calculated for C₁₇ H₂₈ N₂ O₄ S—H₂O: Theory: C, 54.51; H, 8.07.Found: C, 54.20; H, 8.29.

Preparation of Final Title Compound

[0335] The final title compound was prepared in a manner analogous tothe procedure set forth in Example 51 from{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclohexyl}[(methylethyl)sulfonyl]amine(230 mg, 0.65 mmol), 2-propanesulfonyl chloride (111 mg, 1.2 Equiv.),and DBU (148 mg, 1.5 Equiv.), to yield the crude final product (257 mg)as an oil. This material was purified via silica gel chromatographyemploying the Chromatotron® using a 2000 micron rotor while eluting witha solvent of methylene chloride/ethyl acetate 7:3 to yield the titlecompound (91 mg, 31%) as an oil. Ion spray M.S. 461.3 (M*−1).

[0336] Calculated for C₂₀ H₃₄ N₂ O₆ S₂-1/2H₂O: Theory: C, 50.92; H,7.48; N, 5.94. Found: C, 51.19; H, 7.39; N, 5.36.

EXAMPLE 69 Preparation of[2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclohexyl][(methylethyl)sulfonyl]amine

[0337]

[0338] The title compound was prepared in a manner analogous to theprocedure set forth in Example 51 from{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclohexyl}[(methylethyl)sulfonyl]amine(230 mg, 0.65 mmol), 2-methanesulfonyl chloride (93 mg, 1.2 Equiv.), andDBU (148 mg, 1.5 Equiv.), to yield the crude final product (302 mg) asan oil. This material was purified via silica gel chromatographyemploying the Chromatotron® using a 2000 micron rotor while eluting witha solvent of methylene chloride/ethyl acetate 7:3 to yield the titlecompound (167 mg, 59%) as an oil. Ion spray M.S: 433.3 (M*−1).

[0339] Calculated for C₁₈ H₃₀ N₂ O₆ S₂-1/2H₂O: Theory: C, 48.73; H,7.04; N, 6.32. Found: C, 49.05; H, 6.82; N, 6.26.

EXAMPLE 70 Preparation ofN-{2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethyl}acetamide

[0340]

[0341] The title compound is prepared in a manner analogous to theprocedure set forth in Example 53 from{2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclohexyl}[(methylethyl)sulfonyl]amineand acetyl chloride.

EXAMPLE 71 Preparation of[2-fluoro-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclohexyl][(methylethyl)sulfonyl]amine.

[0342]

[0343] The title compound was prepared in a manner analogous to theprocedure set forth in Example 59 from[2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine(155 mg, 0.36 mmol) and DAST (0.01 mL) to provide a cis/trans mixture ofthe title compounds (141 mg) as a foam. This material was separated andpurified via silica gel chromatography employing the Chromatotron® andusing a 4000 micron rotor while eluting with a solvent of methylenechloride/ethyl acetate 4:1 to yield the trans isomer of the titlecompound (80 mg, top spot by TLC) as a white solid. Ion spray M.S. 435.3(M*−1)

[0344] Calculated for C₁₈ H₂₉ N₂ O₅ S₂ F-1/2 H₂O: Theory: C, 47.55; H,6.84; N, 6.16. Found: C, 47.58; H, 6.89; N, 5.65.

[0345] Continued elution afforded a cis/trans mixture (61 mg) as a foam.Ed M.S. 435.3 (M*−1). Calculated for C₁₈ H₂₉ N₂ O₅ S₂ F-1/2 H₂O: Theory:C, 49.52; H, 6.70; N, 6.42. Found: C, 49.17; H, 6.64; N, 6.22.

EXAMPLE 72 Preparation of{2-fluoro-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclohexyl}[methylethyl)sulfonyl]amine

[0346]

[0347] The title compound was prepared in a manner analogous to theprocedure set forth in Example 59 from{2-hydroxy-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine(80 mg, 0.17 mmol) and DAST (0.05 mL) to provide a cis/trans mixture ofthe title compounds (81 mg) as an oil. This material was separated andpurified via silica gel chromatography employing the Chromatotron® andusing a 2000 micron rotor while eluting with a solvent of methylenechloride/ethyl acetate 4:1 to yield the trans isomer of the titlecompound (30 mg, top spot by TLC) as an oil. Ion spray M.S. 463.3(M*−1).

[0348] Calculated for C₂₀ H₃₃ N₂ O₅ S₂ F: Theory: C, 51.70; H, 7.16; N,6.03. Found: C, 51.43; H, 7.16; N, 5.89.

[0349] Continued elution afforded a cis/trans mixture (11 mg) as a foam.Fd M.S. 463.3 (M*−1).

EXAMPLE 73

[0350] Preparation ofN-{2-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethyl}acetamide

[0351] The title compound is prepared in a manner analogous to theprocedure set forth in Example 59 fromN-{2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethyl}acetamide.

EXAMPLE 74 Preparation of(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxacyclohexyl)[(methylethyl)sulfonyl]amine.

[0352]

[0353] The title compound is prepared in a manner analogous to theprocedure set forth in Example 48 from 3,5-difluorobenzyl bromide and[2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine toprovide 511 mg as a brown oil. This material was purified via silica gelchromatography employing the Chromatotron® using a 4000 micron rotorwhile eluting with a solvent of methylene chloride/ethyl acetate 4:1 toyield the title compound (360 mg, 85%) as a white solid. Ion spray M.S.438.3 (M*−1).

[0354] Calculated for C₂₂ H₂₇ N O₄ SF₂: Theory: C, 60.12; H, 6.19; N,3.19. Found: C, 59.32; H, 6.14; N, 3.26.

EXAMPLE 75 Preparation of2-{[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]methyl}benzenecarbonitrile

[0355]

[0356] The title compound is prepared in a manner analogous to theprocedure set forth in Example 48 from 2-cyanobenzyl bromide and[2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine toprovide 501 mg as a brown oil. This material was purified via silica gelchromatography employing the Chromatotron® using a 4000 micron rotorwhile eluting with a solvent of methylene chloride/ethyl acetate 9:1 toyield the title compound (291 mg, 71 %) as a white solid. Ion spray M.S.427.4 (M*−1).

[0357] Calculated for C₂₃ H₂₈ N₂ O₄ S-1/2 H₂O: Theory: C, 63.12; H,6.70; N, 6.40. Found: C, 63.20; H, 6.64; N, 6.28.

EXAMPLE 76 Preparation ofcis-(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-fluorocyclohexyl)[(methylethyl)sulfonyl]amineandtrans-(2-{4-[(3,5-difluorophenyl)methoxyl]phenyl}-2-fluorocyclohexyl)[(methylethyl)sulfonyl]amine

[0358]

[0359] Into a 50 mL 3 neck flask fitted with a stirrer and thermometer,(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxycyclohexyl)[(methylethyl)sulfonyl]amine(350 mg, 0.80 mmol) in CH₂Cl₂ (5 mL) was added dropwise to 0.01 mL DASTin CH₂CL₂ (15 mL) while stirring at −78° C. under a nitrogen atmosphere.The reaction was allowed to warm to room temperature and diluted withCH₂Cl₂ (20 mL). This organic layer was washed with H₂O, dried overNa₂SO₄, filtered, and concentrated under reduced vacuum to yield 351 mgof an oil (2 spots by TLC). This material was separated and purified viasilica gel chromatography employing the Chromatotron® and using a 4000micron rotor while eluting with a solvent of hexane/ethyl acetate 9:1 toyield the trans isomer of the title compound (27 mg, top spot by TLC) asa white solid. Ion spray M.S. 440.2 (M*−1).

[0360] Calculated for C₂₂ H₂₆ N O₃ S F₃: Theory: C, 59.85; H, 5.94; N,3.17. Found: C, 59.02; H, 5.96; N, 3.38.

[0361] Continued elution afforded a cis/trans mixture of the titlecompound (254 mg) as a semi-solid. Fd M.S. 440.2 (M*−1).

EXAMPLE 77 Preparation ofcis-2-{[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]methyl}benzenecarbonitrileand trans-2-{[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]methyl}benzenecarbonitrile

[0362]

[0363] Into a 50 mL 3 neck flask fitted with a stirrer and thermometer,2-([4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]methyl}benzenecarbonitrile(200 mg, 0.47 mmol) in CH₂Cl₂ (5 mL) was added dropwise to 0.05 mL DASTin CH₂CL₂ (15 mL) while stirring at −78° C under a nitrogen atmosphere.The reaction was allowed to warm to room temperature and diluted withCH₂Cl₂ (20 mL). This organic layer was washed with H₂O, dried overNa₂SO₄, filtered, and concentrated under reduced vacuum to yield 178 mgof an oil (2 spots by TLC) This material was separated and purified viasilica gel chromatography employing the Chromatotron® and using a 4000micron rotor while eluting with a solvent of methylene chloride/ethylacetate 9:1 to yield the trans isomer of the title compound (17 mg, topspot by TLC) as a white foam. Ion spray M.S. 429.2 (M*−1). Continuedelution afforded a cis/trans mixture of the title compound (151 mg) as asemi-solid.

[0364] The ability of compounds of formula I to potentiate glutamatereceptor-mediated response may be determined using fluorescent calciumindicator dyes (Molecular Probes, Eugene, Oreg., Fluo-3) and bymeasuring glutamate-evoked efflux of calcium into GluR4 transfectedHEK293 cells, as described in more detail below.

[0365] In one test, 96 well plates containing confluent monolayers ofHEK 293 cells stably expressing human GluR4B (obtained as described inEuropean Patent Application Publication Number EP-A1-583917) areprepared. The tissue culture medium in the wells is then discarded, andthe wells are each washed once with 200 μl of buffer (glucose, 10 mM,sodium chloride, 138 mM, magnesium chloride, 1 mM, potassium chloride, 5mM, calcium chloride, 5 mM,N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], 10 mM, to pH7.1 to 7.3). The plates are then incubated for 60 minutes in the darkwith 20 μM Fluo3-AM dye (obtained from Molecular Probes Inc., Eugene,Oreg.) in buffer in each well. After the incubation, each well is washedonce with 100 μl buffer, 200 μl of buffer is added and the plates areincubated for 30 minutes. Solutions for use in the test are alsoprepared as follows. 30 μM, 10 μM, 3 μM and 1 μM dilutions of testcompound are prepared using buffer from a 10 mM solution of testcompound in DMSO. 100 μM cyclothiazide solution is prepared by adding 3μl of 100 mM cyclothiazide to 3 mL of buffer. Control buffer solution isprepared by adding 1.5 μl DMSO to 498.5 μl of buffer. Each test is thenperformed as follows. 200 μl of control buffer in each well is discardedand replaced with 45 μl of control buffer solution. A baselinefluorescent measurement is taken using a FLUOROSKAN II fluorimeter(Obtained from Labsystems, Needham Heights, Mass., USA, a Division ofLife Sciences International Plc).: The buffer is then removed andreplaced with 45 μl of buffer and 45 μl of test compound in buffer inappropriate wells. A second fluorescent reading is taken after 5 minutesincubation. 15 μl of 400 μM glutamate solution is then added to eachwell (final glutamate concentration 100 μM), and a third reading istaken. The activities of test compounds and cyclothiazide solutions aredetermined by subtracting the second from the third reading(fluorescence due to addition of glutamate in the presence or absence oftest compound or cyclothiazide) and are expressed relative to enhancefluorescence produced by 100 μM cyclothiazide.

[0366] In another test, HEK293 cells stably expressing human GluR4(obtained as described in European Patent Application Publication No.EP-A1-0583917) are used in the electrophysiological characterization ofAMPA receptor potentiators. The extracellular recording solutioncontains (in mM): 140 NaCl, 5 KCl, 10 HEPES, 1 MgCl₂, 2 CaCl₂, 10glucose, pH=7.4 with NaOH, 295 mOsm kg-1. The intracellular recordingsolution contains (in mM): 140 CsCl, 1 MgCl₂, 10 HEPES,(N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA(ethylene-bis(oxyethylene-nitrile)tetraacetic acid), pH=7.2 with CsOH,295 mOsm kg-1. With these solutions, recording pipettes have aresistance of 2-3 MΩ. Using the whole-cell voltage clamp technique(Hamill et al.(1981)Pflügers Arch., 391: 85-100), cells arevoltage-clamped at −60 mV and control current responses to 1 mMglutamate are evoked. Responses to 1 mM glutamate are then determined inthe presence of test compound. Compounds are deemed active in this testif, at a test concentration of 10 μM or less, they produce a greaterthan 10% increase in the value of the current evoked by 1 mM glutamate.

[0367] In order to determine the potency of test compounds, theconcentration of the test compound, both in the bathing solution andco-applied with glutamate, is increased in half log units until themaximum effect was seen. Data collected in this manner are fit to theHill equation, yielding an EC₅₀ value, indicative of the potency of thetest compound. Reversibility of test compound activity is determined byassessing control glutamate 1 mM responses. Once the control responsesto the glutamate challenge are re-established, the potentiation of theseresponses by 100 μM cyclothiazide is determined by its inclusion in boththe bathing solution and the glutamate-containing solution. In thismanner, the efficacy of the test compound relative to that ofcyclothiazide can be determined.

[0368] According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of formula I or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable diluent or carrier.

[0369] The pharmaceutical compositions are prepared by known proceduresusing well-known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier, and may be in the form of a capsule, sachet, paper, orother container. When the carrier serves as a diluent, it may be asolid, semi-solid, or liquid material which acts as a vehicle,excipient, or medium for the active ingredient. The compositions can bein the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointmentscontaining, for example, up to 10% by weight of active compound, softand hard gelatin capsules, suppositories, sterile injectable solutions,and sterile packaged powders.

[0370] Some examples of suitable carriers, excipients, and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum,acacia, calcium phosphate, alginates, tragcanth, gelatin, calciumsilicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose,water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

[0371] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 1 mg to about 500 mg, more preferablyabout 5 mg to about 300 mg (for example 25 mg) of the active ingredient.The term “unit dosage form” refers to a physically discrete unitsuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical carrier, diluent, or excipient. The followingformulation examples are illustrative only and are not intended to limitthe scope of the invention in any way.

Formulation 1

[0372] Hard gelatin capsules are prepared using the followingingredients: Quantify (mg/capsule) Active Ingredient 250 Starch, dried200 Magnesium Stearate 10 Total 460

[0373] The above ingredients are mixed and filled into hard gelatincapsules in 460 mg quantities.

Formulation 2

[0374] Tablets each containing 60 mg of active ingredient are made asfollows: Quantity (mg/tablet) Active Ingredient 60 Starch 45Microcrystalline Cellulose 35 Polyvinylpyrrolidone 4 SodiumCarboxymethyl Starch 4.5 Magnesium Stearate 0.5 Talc 1 Total 150

[0375] As used herein the term “active ingredient” refers to a compoundof formula 1. The active ingredient, starch, and cellulose are passedthrough a No. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

[0376] As used herein the term “patient” refers to a mammal, such as amouse, guinea pig, rat, dog or human. It is understood that thepreferred patient is a human.

[0377] As used herein, the terms “treating” or “to treat” each mean toalleviate symptoms, eliminate the causation either on a temporary orpermanent basis, or to prevent or slow the appearance of symptoms of thenamed disorder. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

[0378] As used herein, the term “effective amount” refers to the amountof a compound of formula I which is effective, upon single or multipledose administration to a patient, in treating the patient suffering fromthe named disorder.

[0379] An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of mammal; its size, age, and general health; thespecific disease or disorder involved; the degree of or involvement orthe severity of the disease or disorder; the response of the individualpatient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

[0380] The compounds can be administered by a variety of routesincluding oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, bucal or intranasal routes. Attentively, the compound maybe administered by continuous infusion. A typical daily dose willcontain from about 0.01 mg/kg to about 100 mg/kg of the active compoundof this invention. Preferably, daily doses will be about 0.05 mg/kg toabout 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.

We claim:
 1. A compound of the formula:

wherein G represents F or OH; R¹ represents an unsubstituted orsubstituted aromatic group, an unsubstituted or substitutedheteroaromatic group, or an unsubstituted or substituted(5-8C)cycloalkyl group; R² represents (1-6C)alkyl, (2-6C)alkenyl, or agroup of formula R³R⁴N in which R³ and R⁴ each independently represent(1-4C)alkyl; and p represents the integer 1 or 2; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein R²represents (1-6C)alkyl.
 3. A compound according to claim 2 wherein R²represents 2-propyl.
 4. A compound according to any of claims 1 to 3wherein p represents
 1. 5. A compound according to any of claims 1 to 3wherein p represents
 2. 6. A compound according to any one of claims 1to 5 wherein G represents F.
 7. A compound according to any one ofclaims 1 to 5 wherein G represents OH.
 8. A compound according to any ofclaims 1 to 7 wherein R¹ represents an unsubstituted or substitutedaromatic group.
 9. A compound according to claim 8 wherein thesubstituted aromatic group is a substituted phenyl.
 10. A compoundaccording to claim 9 wherein the phenyl is substituted with halogen;nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl;halo(1-10C)alkyl; —O—(CH₂)_(t)CN, —O—(CH₂)_(t)NH₂,—O—(CH₂)_(t)NHCOR^(10a), —O—(CH₂)_(t)NHSO₂R^(10a) in which t is aninteger of from 1 to 4; (CH₂)_(y)X¹ R⁹ in which y is 0 or an integer offrom 1 to 4, X¹ represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO,NR¹²COCOO, OCONR¹³, R⁹ represents hydrogen, (1-10C) alkyl,(3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl,morpholino or (3-8C)cycloalkyl and R¹⁰, R^(10a), R¹¹, R¹² and R¹³ eachindependently represents hydrogen or (1-10C)alkyl, or R⁹ and R¹⁰, R¹¹,R¹² or R¹³ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group;N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C)alkylpiperazinyl; thienyl;furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl;pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl;dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl;(1-4C)alkoxycarbonyl dihydrothiazolyl; (1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl;tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl;benzothienyl; benzimidazolyl; and a group of formulaR¹⁴-(L^(a))_(n)-X²-(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; 4-(1,1 -dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷ OCONR¹⁹ orNR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or subsituted byone or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylaminoand (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ each independentlyrepresents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷, R¹⁸ or R¹⁹together with the nitrogen atom to which they are attached form anazetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 11. Acompound according to claim 10 wherein the substituted phenyl issubstituted with a group of formula R¹⁴-(L^(a))_(n)-X²L^(b))_(m) inwhich X² represents a bond, O, NH, S, SO, SO₂, CO, CH(OH), CONH, NHCO,NHCONH, NHCOO, COCONH, OCH₂CONH, or CH═CH, L^(a) and L^(b) eachrepresent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0,and R¹⁴ represents a phenyl or heteroaromatic group which isunsubstituted or substituted by one or two of halogen; nitro; cyano;(1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;4-(1,1-dioxotetrahydro-1,2-thiazinyl); halo(1-10C)alkyl;cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ in which z is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ or NR¹⁹COO, R¹⁵represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl,(1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alklsuffbnylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 12. Acompound according to claim 10 wherein (L^(a))_(n)-X²-(L^(b))_(m)represents a bond, CONH, or CH₂O.
 13. A compound according to claim 12wherein R¹⁴ represents a phenyl which is unsubstituted or substituted byone or two of halogen; nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl;(2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents 0, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹ orNR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl; (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represent hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 14. Acompound according to claim 13 wherein R¹⁴ represents a phenyl which issubstituted by one or two of halogen; nitro; cyano; (1-10C) alkyl;halo(1-10C)alkyl; and (CH₂)_(z)X³R¹⁵ in which z is 0, 1 or 2, X³represents O, NR¹⁶, CO, COO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷,OCONR¹⁹ or NR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl,phenyl(1-4C)alkyl, halo(1-10C)alkyl, or (3-10C)alkenyl, and R¹⁶, R¹⁷,R¹⁸ and R¹⁹ each independently represent hydrogen or (1-10C)alkyl.
 15. Acompound according to claim 14 wherein R¹⁴ represents a phenyl which issubstituted by one or two of fluoro; chloro, cyano; (1-4C)alkyl;trifluoromethyl; and (CH₂)_(z)X³R¹⁵ in which z is 0, or 2, X³ representsNR¹⁶, CO, COO, CONR¹⁷, NR¹⁸CO, NHSO₂R¹⁵ represents hydrogen,(1-4C)alkyl, phenyl(1-4C)alkyl, or halo(1-4C)alkyl, and R¹⁶, R¹⁷, R¹⁸and R¹⁹ each independently represent hydrogen or (1-4C)alkyl.
 16. Acompound according to claim 10 wherein the phenyl is substituted with—O—(CH₂)_(t)NHCOR^(10a), or —O—(CH₂)_(t)NHSO₂R^(10a) in which t is aninteger of from 1 to 4, and R^(10a) represents (1-10C)alkyl.
 17. Acompound according to claim 16 wherein t is
 2. 18. A compound accordingto claim 17 wherein R^(10a) is (1-4C)alkyl.
 19. A compound according toclaim 18 wherein —O—(CH₂)_(t)NHCOR^(10a) and —O—(CH₂)^(t)NHSO₂R^(10a)are at the 4-position on the phenyl ring.
 20. A compound according toclaim 19 wherein R^(10a) is methyl or 2-propyl.
 21. A compound which isselected from the group consisting of:trans-[2-fluoro-2-(4-phenylphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;cis-[2-fluoro-2-(4-phenylphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;trans-[2-fluoro-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amine;trans-[(dimethylamino)sulfonyl][2-fluoro-2-(4-phenylphenyl)cyclopentyl]amine;trans-(2-fluoro-2-phenylcyclohexyl)[(methylethyl)sulfonyl]amine;[2-fluoro-2-(4-nitrophenyl)cyclohexyl][(methylethyl)sulfonyl]amine;[2-fluoro-2-(4-aminophenyl)cyclohexyl][(methylethyl)sulfonyl]amine;(3,5difluorophenyl)-N-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenyl]carboxamide;[2-fluoro-2-(4-bromophenyl)cyclohexyl][(methylethyl)sulfonyl]amine;{2-fluoro-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]cyclohexyl}[(methylethyl)sulfonyl]-amine;[2-fluoro-2-(4-phenylphenyl)cyclopentyl][(methylethyl)sulfonyl]amine;[2-(4-fluorophenyl)-2-hydroxycyclopentyl][(methylethyl)sulfonyl]amine;2-fluoro-2-(4-fluorophenyl)cyclopentyl][(methylethyl)sulfonyl]amine;trans-{2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine;cis-{2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine;[2-hydroxy-2-(4-hydroxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine;trans-(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine;cis-(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine;[2-hydroxy-2-(4-phenoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine;trans-[2-fluoro-2-(4-phenoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine;cis-[2-fluoro-2-(4-phenoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine;[2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine;{2-hydroxy-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine;N-{2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethyl}acetamide;[2-fluoro-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclopentyl][(methylethyl)sulfonyl]amine;{2-fluoro-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclopentyl}[(methylethyl)sulfonyl]amine;N-{2-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethyl}acetamide;2-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile;[2-(4-fluorophenyl)-2-hydroxycyclohexyl][(methylethyl)sulfonyl]amine;trans-[2-fluoro-2-(4-fluorophenyl)cyclohexyl][(methylethyl)sulfonyl]amine;cis-[2-fluoro-2-(4-fluorophenyl)cyclohexyl][(methylethyl)sulfonyl]amine;trans-[2-hydroxy-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;cis-[2-hydroxy-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;trans-{2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclohexyl)[(methylethyl)sulfonyl]amine;cis-{2-hydroxy-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine;trans-[2-hydroxy-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;cis-[2-hydroxy-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;trans-[2-fluoro-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;cis-[2-fluoro-2-(4-methoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;trans-{2-fluoro-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine;cis-{2-fluoro-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine;trans-[2-fluoro-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;cis-[2-fluoro-2-(4-phenoxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;[2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;cis-[2-fluoro-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;trans-[2-fluoro-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine;{2-hydroxy-2-[4-(2-{[(methylethyl)sulfonyl]aminoethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine;[2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclohexyl][(methylethyl)sulfonyl]amine;N-{2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethyl}acetamide;[2-fluoro-2-(4-{2-[methylsulfonyl)amino]ethoxy}phenyl)cyclohexyl][(methylethyl)sulfonyl]amine;{2-fluoro-2-[4-(2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]cyclohexyl)[(methylethyl)sulfonyl]amine;N-{2-[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethyl}acetamide;(2-{4-[(3,5-difluorophenyl)methoxy]phenyl}-2-hydroxycyclohexyl)[(methylethyl)sulfonyl]amine;{[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]methyl}benzenecarbontrile;cis-(2-{4-[(3,5difluorophenyl)methoxy]phenyl}-2-fluorocyclohexyl)[(methylethyl)sulfonyl]amine;trans-(2-}4-[(3,5-difluorophenyl)methoxy]phenyl}-2-fluorocyclohexyl)[(methylethyl)sulfonyl]amine;cis-2-{[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]methyl}benzenecarbonitrile;andtrans-2-{[4-(1-fluoro-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]methyl}benzenecarbonitrile;and the pharmaceutically acceptable salts thereof.
 22. A pharmaceuticalcomposition, which comprises a compound as claimed in any one of claims1 to 21 and a pharmaceutically acceptable diluent or carrier.
 23. Amethod of potentiating glutamate receptor function in a patient, whichcomprises administering to said patient an effective amount of acompound according to claim
 1. 24. A method of treating a cognitivedisorder; Alzheimer's disease, a neuro-degenerative disorder;age-related dementia; age-induced memory impairment; movement disorder;reversal of a drug-induced state; depression; attention deficitdisorder; attention deficit hyperactivity disorder, psychosis; cognitivedeficits associated with psychosis; drug-induced psychosis, or stroke ina patient, which comprises administering to a patient an effectiveamount of a compound according to claim
 1. 25. A compound according toany of claims 1 to 21, or a pharmaceutically acceptable salt thereof,for use as a pharmaceutical.
 26. The use of a compound according to anyof claims 1 to 21, or a pharmaceutically acceptable salt thereof, forthe manufacture of a medicament for potentiating glutamate receptorfunction.
 27. The use of a compound according to any of claims 1 to 21for the manufacture of a medicament for treating a cognitive disorder; aneuro-degenerative disorder; age-related dementia; age-induced memoryimpairment; movement disorder; reversal of a drug-induced state;depression; attention deficit disorder; attention deficit hyperactivitydisorder; psychosis; cognitive deficits associated with psychosis;drug-induced psychosis, or stroke.